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Topical Collection "Neuroprotective Strategies"

Editor

Collection Editor
Prof. Dr. Katalin Prokai-Tatrai

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
Website | E-Mail
Interests: medicinal chemistry: Drug design of CNS agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; estrogens as neuroprotective agents, bioanalytical method development

Topical Collection Information

Dear Colleagues,

We started the “Neuroprotective Strategies” collection jointly with Molecules in 2009. It was a great success; a large number of reviews and original research articles were published in the inaugural volume. Since then, the International Journal of Molecular Sciences has successfully continued this collection covering neuroprotection broadly including, but not limited to, preclinical/basic science assessments of various animal models relevant to diseases and agents with potential or perceived translation values. We open up the “Neuroprotective Strategies” Topical Collection to thought-provoking Comments, Opinions and Perspectives, in addition to our traditional Reviews and Research Articles in this field. We especially encourage submissions that address critical issues having prevented successful clinical translations of promising laboratory data. Limitations of in vitro studies and preclinical animal models to mirror multiple pathologies underlying human neurodegenerative diseases, lack of drug-likeness of experimental agents, the need to consider absorption, distribution, metabolism, elimination, toxicology (ADMET) and pharmacokinetics even in the early stage of drug discovery, as well as obstacles of drug delivery to the CNS are only some of the issues that come to mind regard this matter. Critical reviews on relevant patent literature are also welcome. I give thanks for past contributions and look forward to receiving future contributions on the promising and challenging aspects of the field. The following links: http://www.mdpi.com/journal/ijms/special_issues/Neuroprotective_strategies_collection and http://www.mdpi.com/journal/molecules/special_issues/neuroprotec-strateg point to already published papers within this collection.

Dr. Katalin Prokai-Tatrai
Collection Editor

Manuscript Submission Information

Manuscripts for the topical collection can be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on this website. The topical collection considers regular research articles, short communications and review articles. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page.

Please visit the Instructions for Authors page before submitting a manuscript. The article processing charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs).


Keywords

  • age-related neurodegeneration

  • blood-brain barrier

  • CNS injury

  • cognition and dementia

  • drug delivery and drug-likeness

  • inflammation

  • in silico drug design and disease models

  • ischemia and reperfusion

  • oxidative stress

  • peripheral nervous system

  • stem cell

  • structure-activity relationship

  • translational medicine

Related Special Issues

Published Papers (150 papers)

2018

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Open AccessArticle Administration of Oxygen Ultra-Fine Bubbles Improves Nerve Dysfunction in a Rat Sciatic Nerve Crush Injury Model
Int. J. Mol. Sci. 2018, 19(5), 1395; https://doi.org/10.3390/ijms19051395
Received: 8 April 2018 / Revised: 29 April 2018 / Accepted: 3 May 2018 / Published: 7 May 2018
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Abstract
Ultra-fine bubbles (<200 nm in diameter) have several unique properties and have been tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUBs) on a sciatic nerve crush injury (SNC) model rats. Rats
[...] Read more.
Ultra-fine bubbles (<200 nm in diameter) have several unique properties and have been tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUBs) on a sciatic nerve crush injury (SNC) model rats. Rats were intraperitoneally injected with 1.5 mL saline, OUBs diluted in saline, or nitrogen ultra-fine bubbles (NUBs) diluted in saline three times per week for 4 weeks in four groups: (1) control, (sham operation + saline); (2) SNC, (crush + saline); (3) SNC+OUB, (crush + OUB-saline); (4) SNC+NUB, (crush + NUB-saline). The effects of the OUBs on dorsal root ganglion (DRG) neurons and Schwann cells (SCs) were examined by serial dilution of OUB medium in vitro. Sciatic functional index, paw withdrawal thresholds, nerve conduction velocity, and myelinated axons were significantly decreased in the SNC group compared to the control group; these parameters were significantly improved in the SNC+OUB group, although NUB treatment did not affect these parameters. In vitro, OUBs significantly promoted neurite outgrowth in DRG neurons by activating AKT signaling and SC proliferation by activating ERK1/2 and JNK/c-JUN signaling. OUBs may improve nerve dysfunction in SNC rats by promoting neurite outgrowth in DRG neurons and SC proliferation. Full article
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Open AccessReview Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis
Int. J. Mol. Sci. 2018, 19(2), 631; https://doi.org/10.3390/ijms19020631
Received: 1 February 2018 / Revised: 18 February 2018 / Accepted: 21 February 2018 / Published: 23 February 2018
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Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial
[...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS. Full article
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Open AccessArticle The Differentiation of Rat Oligodendroglial Cells Is Highly Influenced by the Oxygen Tension: In Vitro Model Mimicking Physiologically Normoxic Conditions
Int. J. Mol. Sci. 2018, 19(2), 331; https://doi.org/10.3390/ijms19020331
Received: 19 December 2017 / Revised: 15 January 2018 / Accepted: 18 January 2018 / Published: 24 January 2018
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Abstract
Oligodendrocyte progenitor cells (OPCs) constitute one of the main populations of dividing cells in the central nervous system (CNS). Physiologically, OPCs give rise to mature, myelinating oligodendrocytes and confer trophic support to their neighboring cells within the nervous tissue. OPCs are known to
[...] Read more.
Oligodendrocyte progenitor cells (OPCs) constitute one of the main populations of dividing cells in the central nervous system (CNS). Physiologically, OPCs give rise to mature, myelinating oligodendrocytes and confer trophic support to their neighboring cells within the nervous tissue. OPCs are known to be extremely sensitive to the influence of exogenous clues which might affect their crucial biological processes, like survival, proliferation, differentiation, and the ability to generate a myelin membrane. Alterations in their differentiation influencing their final potential for myelinogenesis are usually the leading cause of CNS dys- and demyelination, contributing to the development of leukodystrophic disorders. The evaluation of the mechanisms that cause oligodendrocytes to malfunction requires detailed studies based on designed in vitro models. Since OPCs readily respond to changes in local homeostasis, it is crucial to establish restricted culture conditions to eliminate the potential stimuli that might influence oligodendrocyte biology. Additionally, the in vitro settings should mimic the physiological conditions to enable the obtained results to be translated to future preclinical studies. Therefore, the aim of our study was to investigate OPC differentiation in physiological normoxia (5% O2) and a restricted in vitro microenvironment. To evaluate the impact of the combined microenvironmental clues derived from other components of the nervous tissue, which are also influenced by the local oxygen concentration, the process of generating OPCs was additionally analyzed in organotypic hippocampal slices. The obtained results show that OPC differentiation, although significantly slowed down, proceeded correctly through its typical stages in the physiologically relevant conditions created in vitro. The established settings were also conducive to efficient cell proliferation, exerting also a neuroprotective effect by promoting the proliferation of neurons. In conclusion, the performed studies show how oxygen tension influences OPC proliferation, differentiation, and their ability to express myelin components, and should be taken into consideration while planning preclinical studies, e.g., to examine neurotoxic compounds or to test neuroprotective strategies. Full article
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Open AccessReview Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions
Int. J. Mol. Sci. 2018, 19(1), 325; https://doi.org/10.3390/ijms19010325
Received: 22 December 2017 / Revised: 15 January 2018 / Accepted: 18 January 2018 / Published: 22 January 2018
Cited by 1 | PDF Full-text (2232 KB) | HTML Full-text | XML Full-text
Abstract
Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement
[...] Read more.
Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed. Full article
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2017

Jump to: 2018, 2016, 2015, 2014, 2013, 2012, 2011, 2010, 2009

Open AccessReview Potential Neuroprotective Effects of Adiponectin in Alzheimer’s Disease
Int. J. Mol. Sci. 2017, 18(3), 592; https://doi.org/10.3390/ijms18030592
Received: 23 December 2016 / Revised: 20 February 2017 / Accepted: 28 February 2017 / Published: 9 March 2017
Cited by 2 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text
Abstract
The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated
[...] Read more.
The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated in AD. Emerging insights into the mechanistic roles of adiponectin and AD highlight the potential therapeutic effects for AD through insulin signaling. Full article
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Open AccessReview Progranulin and Its Related MicroRNAs after Status Epilepticus: Possible Mechanisms of Neuroprotection
Int. J. Mol. Sci. 2017, 18(3), 490; https://doi.org/10.3390/ijms18030490
Received: 24 December 2016 / Revised: 9 February 2017 / Accepted: 15 February 2017 / Published: 24 February 2017
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Abstract
The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins
[...] Read more.
The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins in the CSF such as progranulin, which is, e.g., responsible for neurite outgrowth and limiting exceeding neuroinflammatory responses, have given us new insights into putative neuroprotective mechanisms following status epilepticus. This should complement the animal data. In this review, we cover what is known about the role of progranulin as well as the links between microRNA changes and the progranulin pathway following status epilepticus in humans and animals hypothesizing neuroprotective and neurorehabilitative effects. Progranulin has also been found to feature prominently in the neuroprotective processes under hypoxic conditions and initiating neurorehabilitative processes. These properties may be used therapeutically, e.g., through drugs that raise the progranulin levels and therefore the cerebral progranulin levels as well with the goal of improving the outcome after status epilepticus. Full article
Open AccessArticle Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats
Int. J. Mol. Sci. 2017, 18(2), 406; https://doi.org/10.3390/ijms18020406
Received: 22 December 2016 / Revised: 1 February 2017 / Accepted: 6 February 2017 / Published: 14 February 2017
Cited by 4 | PDF Full-text (8572 KB) | HTML Full-text | XML Full-text
Abstract
Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study
[...] Read more.
Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life. Full article
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Open AccessArticle Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model
Int. J. Mol. Sci. 2017, 18(2), 245; https://doi.org/10.3390/ijms18020245
Received: 5 December 2016 / Revised: 5 January 2017 / Accepted: 15 January 2017 / Published: 25 January 2017
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Abstract
Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study
[...] Read more.
Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS−/− knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS−/− mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS−/− mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation. Full article
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Open AccessArticle α-Tocopherol at Nanomolar Concentration Protects Cortical Neurons against Oxidative Stress
Int. J. Mol. Sci. 2017, 18(1), 216; https://doi.org/10.3390/ijms18010216
Received: 28 September 2016 / Revised: 8 January 2017 / Accepted: 14 January 2017 / Published: 21 January 2017
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Abstract
The aim of the present work is to study the mechanism of the α-tocopherol (α-T) protective action at nanomolar and micromolar concentrations against H2O2-induced brain cortical neuron death. The mechanism of α-T action on neurons at its nanomolar concentrations
[...] Read more.
The aim of the present work is to study the mechanism of the α-tocopherol (α-T) protective action at nanomolar and micromolar concentrations against H2O2-induced brain cortical neuron death. The mechanism of α-T action on neurons at its nanomolar concentrations characteristic for brain extracellular space has not been practically studied yet. Preincubation with nanomolar and micromolar α-T for 18 h was found to increase the viability of cortical neurons exposed to H2O2; α-T effect was concentration-dependent in the nanomolar range. However, preincubation with nanomolar α-T for 30 min was not effective. Nanomolar and micromolar α-T decreased the reactive oxygen species accumulation induced in cortical neurons by the prooxidant. Using immunoblotting it was shown that preincubation with α-T at nanomolar and micromolar concentrations for 18 h prevented Akt inactivation and decreased PKCδ activation induced in cortical neurons by H2O2. α-T prevented the ERK1/2 sustained activation during 24 h caused by H2O2. α-T at nanomolar and micromolar concentrations prevented a great increase of the proapoptotic to antiapoptotic proteins (Bax/Bcl-2) ratio, elicited by neuron exposure to H2O2. The similar neuron protection mechanism by nanomolar and micromolar α-T suggests that a “more is better” approach to patients’ supplementation with vitamin E or α-T is not reasonable. Full article
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Open AccessArticle Neuroprotective and Anti-Apoptotic Effects of CSP-1103 in Primary Cortical Neurons Exposed to Oxygen and Glucose Deprivation
Int. J. Mol. Sci. 2017, 18(1), 184; https://doi.org/10.3390/ijms18010184
Received: 11 October 2016 / Revised: 3 January 2017 / Accepted: 12 January 2017 / Published: 18 January 2017
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Abstract
CSP-1103 (formerly CHF5074) has been shown to reverse memory impairment and reduce amyloid plaque as well as inflammatory microglia activation in preclinical models of Alzheimer’s disease. Moreover, it was found to improve cognition and reduce brain inflammation in patients with mild cognitive impairment.
[...] Read more.
CSP-1103 (formerly CHF5074) has been shown to reverse memory impairment and reduce amyloid plaque as well as inflammatory microglia activation in preclinical models of Alzheimer’s disease. Moreover, it was found to improve cognition and reduce brain inflammation in patients with mild cognitive impairment. Recent evidence suggests that CSP-1103 acts through a single molecular target, the amyloid precursor protein intracellular domain (AICD), a transcriptional regulator implicated in inflammation and apoptosis. We here tested the possible anti-apoptotic and neuroprotective activity of CSP-1103 in a cell-based model of post-ischemic injury, wherein the primary mouse cortical neurons were exposed to oxygen-glucose deprivation (OGD). When added after OGD, CSP-1103 prevented the apoptosis cascade by reducing cytochrome c release and caspase-3 activation and the secondary necrosis. Additionally, CSP-1103 limited earlier activation of p38 and nuclear factor κB (NF-κB) pathways. These results demonstrate that CSP-1103 is neuroprotective in a model of post-ischemic brain injury and provide further mechanistic insights as regards its ability to reduce apoptosis and potential production of pro-inflammatory cytokines. In conclusion, these findings suggest a potential use of CSP-1103 for the treatment of brain ischemia. Full article
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Open AccessArticle Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion
Int. J. Mol. Sci. 2017, 18(1), 3; https://doi.org/10.3390/ijms18010003
Received: 4 October 2016 / Revised: 16 November 2016 / Accepted: 6 December 2016 / Published: 17 January 2017
Cited by 4 | PDF Full-text (13561 KB) | HTML Full-text | XML Full-text
Abstract
Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic
[...] Read more.
Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit. Full article
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2016

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Open AccessReview Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women
Int. J. Mol. Sci. 2016, 17(12), 2147; https://doi.org/10.3390/ijms17122147
Received: 18 October 2016 / Revised: 7 December 2016 / Accepted: 13 December 2016 / Published: 20 December 2016
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Abstract
Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general
[...] Read more.
Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer’s disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health. Full article
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Open AccessArticle Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid
Int. J. Mol. Sci. 2016, 17(12), 2129; https://doi.org/10.3390/ijms17122129
Received: 25 July 2016 / Revised: 5 December 2016 / Accepted: 9 December 2016 / Published: 17 December 2016
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Abstract
Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important
[...] Read more.
Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS. Full article
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Open AccessReview Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies
Int. J. Mol. Sci. 2016, 17(12), 2078; https://doi.org/10.3390/ijms17122078
Received: 13 October 2016 / Revised: 2 December 2016 / Accepted: 6 December 2016 / Published: 10 December 2016
Cited by 15 | PDF Full-text (613 KB) | HTML Full-text | XML Full-text
Abstract
Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply
[...] Read more.
Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches. Full article
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Open AccessArticle Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice
Int. J. Mol. Sci. 2016, 17(12), 2066; https://doi.org/10.3390/ijms17122066
Received: 31 August 2016 / Revised: 28 November 2016 / Accepted: 6 December 2016 / Published: 9 December 2016
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Abstract
Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that
[...] Read more.
Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA. Full article
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Open AccessArticle The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons
Int. J. Mol. Sci. 2016, 17(12), 2005; https://doi.org/10.3390/ijms17122005
Received: 2 September 2016 / Revised: 16 November 2016 / Accepted: 17 November 2016 / Published: 30 November 2016
Cited by 1 | PDF Full-text (1673 KB) | HTML Full-text | XML Full-text
Abstract
Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a
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Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. Results: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult. Full article
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Open AccessReview Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans
Int. J. Mol. Sci. 2016, 17(12), 1981; https://doi.org/10.3390/ijms17121981
Received: 1 September 2016 / Revised: 11 November 2016 / Accepted: 21 November 2016 / Published: 26 November 2016
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Abstract
Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our
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Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising. Full article
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Open AccessReview Neuroprotective Strategies during Cardiac Surgery with Cardiopulmonary Bypass
Int. J. Mol. Sci. 2016, 17(11), 1945; https://doi.org/10.3390/ijms17111945
Received: 21 July 2016 / Revised: 2 November 2016 / Accepted: 15 November 2016 / Published: 21 November 2016
Cited by 4 | PDF Full-text (374 KB) | HTML Full-text | XML Full-text
Abstract
Aortocoronary bypass or valve surgery usually require cardiac arrest using cardioplegic solutions. Although, in principle, in a number of cases beating heart surgery (so-called off-pump technique) is possible, aortic or valve surgery or correction of congenital heart diseases mostly require cardiopulmonary arrest. During
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Aortocoronary bypass or valve surgery usually require cardiac arrest using cardioplegic solutions. Although, in principle, in a number of cases beating heart surgery (so-called off-pump technique) is possible, aortic or valve surgery or correction of congenital heart diseases mostly require cardiopulmonary arrest. During this condition, the heart-lung machine also named cardiopulmonary bypass (CPB) has to take over the circulation. It is noteworthy that the invention of a machine bypassing the heart and lungs enabled complex cardiac operations, but possible negative effects of the CPB on other organs, especially the brain, cannot be neglected. Thus, neuroprotection during CPB is still a matter of great interest. In this review, we will describe the impact of CPB on the brain and focus on pharmacological and non-pharmacological strategies to protect the brain. Full article
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Open AccessArticle Protective Effect of Tempol against Cisplatin-Induced Ototoxicity
Int. J. Mol. Sci. 2016, 17(11), 1931; https://doi.org/10.3390/ijms17111931
Received: 9 August 2016 / Revised: 1 November 2016 / Accepted: 15 November 2016 / Published: 18 November 2016
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Abstract
One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell
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One of the major adverse effects of cisplatin chemotherapy is hearing loss. Cisplatin-induced ototoxicity hampers treatment because it often necessitates dose reduction, which decreases cisplatin efficacy. This study was performed to investigate the effect of Tempol on cisplatin-induced ototoxicity in an auditory cell line, House Ear Institute-Organ of Corti 1 (HEI-OC1). Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 24 h with or without a 2 h pre-treatment with Tempol. Cell viability was determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and apoptotic cells were identified using terminal deoxynucleotidyl transferase dUTP nick end labeling of nuclei (TUNEL) assay and flow cytometry. The effects of Tempol on cisplatin-induced cleaved poly(ADP-ribose) polymerase, cleaved caspase, and mitochondrial inducible nitric oxide synthase expression were evaluated using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured to assess the effects of Tempol on cisplatin-induced ROS accumulation. Mitochondria were evaluated by confocal microscopy, and the mitochondrial membrane potential was measured to investigate whether Tempol protected against cisplatin-induced mitochondrial dysfunction. Cisplatin treatment decreased cell viability, and increased apoptotic features and markers, ROS accumulation, and mitochondrial dysfunction. Tempol pre-treatment before cisplatin exposure significantly inhibited all these cisplatin-induced effects. These results demonstrate that Tempol inhibits cisplatin-induced cytotoxicity in HEI-OC1, and could play a preventive role against cisplatin-induced ototoxicity. Full article
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Open AccessArticle Salvianolic Acid B (Sal B) Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Cell Death by Activating Glutaredoxin 1 (Grx1)
Int. J. Mol. Sci. 2016, 17(11), 1835; https://doi.org/10.3390/ijms17111835
Received: 14 July 2016 / Revised: 8 October 2016 / Accepted: 31 October 2016 / Published: 3 November 2016
Cited by 5 | PDF Full-text (4071 KB) | HTML Full-text | XML Full-text
Abstract
Protein glutathionylation, defined as the formation of protein mixed disulfides (PSSG) between cysteine residues and glutathione (GSH), can lead to cell death. Glutaredoxin 1 (Grx1) is a thiol repair enzyme which catalyzes the reduction of PSSG. Therefore, Grx1 exerts strong anti-apoptotic effects by
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Protein glutathionylation, defined as the formation of protein mixed disulfides (PSSG) between cysteine residues and glutathione (GSH), can lead to cell death. Glutaredoxin 1 (Grx1) is a thiol repair enzyme which catalyzes the reduction of PSSG. Therefore, Grx1 exerts strong anti-apoptotic effects by improving the redox state, especially in times of oxidative stress. However, there is currently no compound that is identified as a Grx1 activator. In this study, we identified and characterized Salvianolic acid B (Sal B), a natural compound, as a Grx1 inducer, which potently protected retinal pigment epithelial (RPE) cells from oxidative injury. Our results showed that treatment with Sal B protected primary human RPE cells from H2O2-induced cell damage. Interestingly, we found Sal B pretreatment upregulated Grx1 expression in RPE cells in a time- and dose-dependent manner. Furthermore, NF-E2-related factor 2 (Nrf2), the key transcription factor that regulates the expression of Grx1, was activated in Sal B treated RPE cells. Further investigation showed that knockdown of Grx1 by small interfering RNA (siRNA) significantly reduced the protective effects of Sal B. We conclude that Sal B protects RPE cells against H2O2-induced cell injury through Grx1 induction by activating Nrf2 pathway, thus preventing lethal accumulation of PSSG and reversing oxidative damage. Full article
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Open AccessArticle The Neuroprotective Properties of Hericium erinaceus in Glutamate-Damaged Differentiated PC12 Cells and an Alzheimer’s Disease Mouse Model
Int. J. Mol. Sci. 2016, 17(11), 1810; https://doi.org/10.3390/ijms17111810
Received: 20 August 2016 / Revised: 14 October 2016 / Accepted: 20 October 2016 / Published: 1 November 2016
Cited by 14 | PDF Full-text (4113 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Hericium erinaceus, an edible and medicinal mushroom, displays various pharmacological activities in the prevention of dementia in conditions such as Parkinson’s and Alzheimer’s disease. The present study explored the neuroprotective effects of H. erinaceus mycelium polysaccharide-enriched aqueous extract (HE) on an l
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Hericium erinaceus, an edible and medicinal mushroom, displays various pharmacological activities in the prevention of dementia in conditions such as Parkinson’s and Alzheimer’s disease. The present study explored the neuroprotective effects of H. erinaceus mycelium polysaccharide-enriched aqueous extract (HE) on an l-glutamic acid (l-Glu)-induced differentiated PC12 (DPC12) cellular apoptosis model and an AlCl3 combined with d-galactose-induced Alzheimer’s disease mouse model. The data revealed that HE successfully induced PC12 cell differentiation. A 3 h HE incubation at doses of 50 and 100 µg/mL before 25 mM of l-Glu effectively reversed the reduction of cell viability and the enhancement of the nuclear apoptosis rate in DPC12 cells. Compared with l-Glu-damaged cells, in PC12 cells, HE suppressed intracellular reactive oxygen species accumulation, blocked Ca2+ overload and prevented mitochondrial membrane potential (MMP) depolarization. In the Alzheimer’s disease mouse model, HE administration enhanced the horizontal and vertical movements in the autonomic activity test, improved the endurance time in the rotarod test, and decreased the escape latency time in the water maze test. It also improved the central cholinergic system function in the Alzheimer’s mice, demonstrated by the fact that it dose-dependently enhanced the acetylcholine (Ach) and choline acetyltransferase (ChAT) concentrations in both the serum and the hypothalamus. Our findings provide experimental evidence that HE may provide neuroprotective candidates for treating or preventing neurodegenerative diseases. Full article
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Open AccessReview The Molecular Pathway of Argon-Mediated Neuroprotection
Int. J. Mol. Sci. 2016, 17(11), 1816; https://doi.org/10.3390/ijms17111816
Received: 13 August 2016 / Revised: 17 October 2016 / Accepted: 25 October 2016 / Published: 31 October 2016
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Abstract
The noble gas argon has attracted increasing attention in recent years, especially because of its neuroprotective properties. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in
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The noble gas argon has attracted increasing attention in recent years, especially because of its neuroprotective properties. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals, argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. As an inert molecule, argon did not show signs of adverse effects in the in vitro and in vivo model used, while being comparably cheap and easy to apply. However, the molecular mechanism by which argon is able to exert its protective and beneficial characteristics remains unclear. Although there are many pieces missing to complete the signaling pathway throughout the cell, it is the aim of this review to summarize the known parts of the molecular pathways and to combine them to provide a clear insight into the cellular pathway, starting with the receptors that may be involved in mediating argons effects and ending with the translational response. Full article
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Open AccessArticle Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress
Int. J. Mol. Sci. 2016, 17(10), 1523; https://doi.org/10.3390/ijms17101523
Received: 25 July 2016 / Revised: 30 August 2016 / Accepted: 4 September 2016 / Published: 24 October 2016
Cited by 5 | PDF Full-text (2909 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated
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Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca2+ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca2+ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca2+ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca2+ release and ER stress. Full article
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Open AccessArticle Auraptene and Other Prenyloxyphenylpropanoids Suppress Microglial Activation and Dopaminergic Neuronal Cell Death in a Lipopolysaccharide-Induced Model of Parkinson’s Disease
Int. J. Mol. Sci. 2016, 17(10), 1716; https://doi.org/10.3390/ijms17101716
Received: 31 August 2016 / Revised: 28 September 2016 / Accepted: 8 October 2016 / Published: 17 October 2016
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Abstract
In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that
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In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4′-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD. Full article
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Open AccessReview Essential Roles of Natural Products and Gaseous Mediators on Neuronal Cell Death or Survival
Int. J. Mol. Sci. 2016, 17(10), 1652; https://doi.org/10.3390/ijms17101652
Received: 31 August 2016 / Revised: 21 September 2016 / Accepted: 22 September 2016 / Published: 29 September 2016
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Abstract
Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key factors associated with degenerative disorders, such as glutamate toxicity and oxidative stress, have been recently identified. Accordingly, there has been growing interest in examining the effects of exogenous and endogenous molecules
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Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key factors associated with degenerative disorders, such as glutamate toxicity and oxidative stress, have been recently identified. Accordingly, there has been growing interest in examining the effects of exogenous and endogenous molecules on neuroprotection and neurodegeneration. In this paper, we review recent studies on neuroprotective and/or neurodegenerative effects of natural products, such as caffeic acid and chlorogenic acid, and gaseous mediators, including hydrogen sulfide and nitric oxide. Furthermore, possible molecular mechanisms of these molecules in relation to glutamate signals are discussed. Insight into the pathophysiological role of these molecules will make progress in our understanding of molecular mechanisms underlying neurodegenerative diseases, and is expected to lead to potential therapeutic approaches. Full article
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Open AccessReview Protein Kinases and Parkinson’s Disease
Int. J. Mol. Sci. 2016, 17(9), 1585; https://doi.org/10.3390/ijms17091585
Received: 30 May 2016 / Revised: 9 August 2016 / Accepted: 1 September 2016 / Published: 20 September 2016
Cited by 5 | PDF Full-text (597 KB) | HTML Full-text | XML Full-text
Abstract
Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson’s disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved
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Currently, the lack of new drug candidates for the treatment of major neurological disorders such as Parkinson’s disease has intensified the search for drugs that can be repurposed or repositioned for such treatment. Typically, the search focuses on drugs that have been approved and are used clinically for other indications. Kinase inhibitors represent a family of popular molecules for the treatment and prevention of various cancers, and have emerged as strong candidates for such repurposing because numerous serine/threonine and tyrosine kinases have been implicated in the pathobiology of Parkinson’s disease. This review focuses on various kinase-dependent pathways associated with the expression of Parkinson’s disease pathology, and evaluates how inhibitors of these pathways might play a major role as effective therapeutic molecules. Full article
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Open AccessReview The Role of Cyclo(His-Pro) in Neurodegeneration
Int. J. Mol. Sci. 2016, 17(8), 1332; https://doi.org/10.3390/ijms17081332
Received: 4 July 2016 / Revised: 4 August 2016 / Accepted: 8 August 2016 / Published: 12 August 2016
Cited by 2 | PDF Full-text (1139 KB) | HTML Full-text | XML Full-text
Abstract
Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events
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Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function. Full article
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Open AccessArticle Cytoprotection against Hypoxic and/or MPP+ Injury: Effect of δ–Opioid Receptor Activation on Caspase 3
Int. J. Mol. Sci. 2016, 17(8), 1179; https://doi.org/10.3390/ijms17081179
Received: 5 June 2016 / Revised: 13 July 2016 / Accepted: 13 July 2016 / Published: 9 August 2016
Cited by 2 | PDF Full-text (2772 KB) | HTML Full-text | XML Full-text
Abstract
The pathological changes of Parkinson’s disease (PD) are, at least partially, associated with the dysregulation of PTEN-induced putative kinase 1 (PINK1) and caspase 3. Since hypoxic and neurotoxic insults are underlying causes of PD, and since δ-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic
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The pathological changes of Parkinson’s disease (PD) are, at least partially, associated with the dysregulation of PTEN-induced putative kinase 1 (PINK1) and caspase 3. Since hypoxic and neurotoxic insults are underlying causes of PD, and since δ-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic insults, we sought to determine whether DOR activation could protect the cells from damage induced by hypoxia and/or MPP+ by regulating PINK1 and caspase 3 expressions. We exposed PC12 cells to either severe hypoxia (0.5%–1% O2) for 24–48 h or to MPP+ at different concentrations (0.5, 1, 2 mM) and then detected the levels of PINK1 and cleaved caspase 3. Both hypoxia and MPP+ reduced cell viability, progressively suppressed the expression of PINK1 and increased the cleaved caspase 3. DOR activation using UFP-512, effectively protected the cells from hypoxia and/or MPP+ induced injury, reversed the reduction in PINK1 protein and significantly attenuated the increase in the cleaved caspase 3. On the other hand, the application of DOR antagonist, naltrindole, greatly decreased cell viability and increased cleaved caspase 3. These findings suggest that DOR is cytoprotective against both hypoxia and MPP+ through the regulation of PINK1 and caspase 3 pathways. Full article
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Open AccessArticle Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury
Int. J. Mol. Sci. 2016, 17(7), 1190; https://doi.org/10.3390/ijms17071190
Received: 9 May 2016 / Revised: 18 July 2016 / Accepted: 18 July 2016 / Published: 22 July 2016
Cited by 8 | PDF Full-text (1738 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and
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This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co-administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway. Full article
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Open AccessArticle Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons
Int. J. Mol. Sci. 2016, 17(7), 1100; https://doi.org/10.3390/ijms17071100
Received: 1 May 2016 / Revised: 10 June 2016 / Accepted: 4 July 2016 / Published: 12 July 2016
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Abstract
Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the
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Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies. Full article
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Open AccessArticle Neuroprotective Effect of Puerarin on Glutamate-Induced Cytotoxicity in Differentiated Y-79 Cells via Inhibition of ROS Generation and Ca2+ Influx
Int. J. Mol. Sci. 2016, 17(7), 1109; https://doi.org/10.3390/ijms17071109
Received: 11 May 2016 / Revised: 29 June 2016 / Accepted: 7 July 2016 / Published: 11 July 2016
Cited by 5 | PDF Full-text (3070 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca2+ influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu
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Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca2+ influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu root, has been widely used in the clinical treatment of retinal degenerative diseases in China for decades; however, the detailed molecular mechanism underlying this effect remains unclear. In this study, the neuroprotective effect of puerarin against glutamate-induced cytotoxicity in the differentiated Y-79 cells was first investigated through cytotoxicity assay. Then the molecular mechanism of this effect regarding anti-oxidative stress and Ca2+ hemostasis was further explored with indirect immunofluorescence, flow cytometric analysis and western blot analysis. Our study showed that glutamate induced cell viability loss, excessive reactive oxygen species (ROS) generation, calcium overload and up-regulated cell apoptosis in differentiated Y-79 cells, which effect was significantly attenuated with the pre-treatment of puerarin in a dose-dependent manner. Furthermore, our data indicated that the neuroprotective effect of puerarin was potentially mediated through the inhibition of glutamate-induced activation of mitochondrial-dependent signaling pathway and calmodulin-dependent protein kinase II (CaMKII)-dependent apoptosis signal-regulating kinase 1(ASK-1)/c-Jun N-terminal kinase (JNK)/p38 signaling pathway. The present study supports the notion that puerarin may be a promising neuroprotective agent in the prevention of retinal degenerative diseases. Full article
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Open AccessArticle Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease
Int. J. Mol. Sci. 2016, 17(7), 1035; https://doi.org/10.3390/ijms17071035
Received: 12 April 2016 / Revised: 13 June 2016 / Accepted: 20 June 2016 / Published: 30 June 2016
Cited by 7 | PDF Full-text (1374 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived
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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL49) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25–35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD. Full article
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Open AccessArticle Echinacoside Inhibits Glutamate Release by Suppressing Voltage-Dependent Ca2+ Entry and Protein Kinase C in Rat Cerebrocortical Nerve Terminals
Int. J. Mol. Sci. 2016, 17(7), 1006; https://doi.org/10.3390/ijms17071006
Received: 10 May 2016 / Revised: 16 June 2016 / Accepted: 20 June 2016 / Published: 24 June 2016
Cited by 6 | PDF Full-text (1465 KB) | HTML Full-text | XML Full-text
Abstract
The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve
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The glutamatergic system may be involved in the effects of neuroprotectant therapies. Echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Herba Cistanche, has neuroprotective effects. This study investigated the effects of echinacoside on 4-aminopyridine-evoked glutamate release in rat cerebrocortical nerve terminals (synaptosomes). Echinacoside inhibited Ca2+-dependent, but not Ca2+-independent, 4-aminopyridine-evoked glutamate release in a concentration-dependent manner. Echinacoside also reduced the 4-aminopyridine-evoked increase in cytoplasmic free Ca2+ concentration but did not alter the synaptosomal membrane potential. The inhibitory effect of echinacoside on 4-aminopyridine-evoked glutamate release was prevented by ω-conotoxin MVIIC, a wide-spectrum blocker of Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but was insensitive to the intracellular Ca2+ release-inhibitors dantrolene and 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157). Furthermore, echinacoside decreased the 4-aminopyridine-induced phosphorylation of protein kinase C, and protein kinase C inhibitors abolished the effect of echinacoside on glutamate release. According to these results, we suggest that the inhibitory effect of echinacoside on evoked glutamate release is associated with reduced voltage-dependent Ca2+ entry and subsequent suppression of protein kinase C activity. Full article
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Open AccessReview Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives
Int. J. Mol. Sci. 2016, 17(6), 904; https://doi.org/10.3390/ijms17060904
Received: 25 April 2016 / Revised: 27 May 2016 / Accepted: 30 May 2016 / Published: 8 June 2016
Cited by 16 | PDF Full-text (334 KB) | HTML Full-text | XML Full-text
Abstract
Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that
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Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology. Full article
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Open AccessArticle Mechanism of Mitochondrial Connexin43′s Protection of the Neurovascular Unit under Acute Cerebral Ischemia-Reperfusion Injury
Int. J. Mol. Sci. 2016, 17(5), 679; https://doi.org/10.3390/ijms17050679
Received: 4 April 2016 / Revised: 27 April 2016 / Accepted: 29 April 2016 / Published: 5 May 2016
Cited by 6 | PDF Full-text (3457 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We observed mitochondrial connexin43 (mtCx43) expression under cerebral ischemia-reperfusion (I/R) injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO). Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride
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We observed mitochondrial connexin43 (mtCx43) expression under cerebral ischemia-reperfusion (I/R) injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO). Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride staining, and cell apoptosis was observed by transferase dUTP nick end labeling. We used transmission electron microscopy to observe mitochondrial morphology and determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. MtCx43, p-mtCx43, protein kinase C (PKC), and p-PKC expression were detected by Western blot. Compared with those in the IR group, cerebral infarction volumes in the carbenoxolone (CBX) and diazoxide (DZX) groups were obviously smaller, and the apoptosis indices were down-regulated. Mitochondrial morphology was damaged after I/R, especially in the IR and 5-hydroxydecanoic acid (5-HD) groups. Similarly, decreased SOD activity and increased MDA were observed after MCAO; CBX, DZX, and phorbol-12-myristate-13-acetate (PMA) reduced mitochondrial functional injury. Expression of mtCx43 and p-mtCx43 and the p-Cx43/Cx43 ratio were significantly lower in the IR group than in the sham group. These abnormalities were ameliorated by CBX, DZX, and PMA. MtCx43 may protect the neurovascular unit from acute cerebral IR injury via PKC activation induced by mitoKATP channel agonists. Full article
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Open AccessArticle Anti-Inflammatory and Cytoprotective Effects of TMC-256C1 from Marine-Derived Fungus Aspergillus sp. SF-6354 via up-Regulation of Heme Oxygenase-1 in Murine Hippocampal and Microglial Cell Lines
Int. J. Mol. Sci. 2016, 17(4), 529; https://doi.org/10.3390/ijms17040529
Received: 29 February 2016 / Revised: 18 March 2016 / Accepted: 25 March 2016 / Published: 8 April 2016
Cited by 3 | PDF Full-text (3840 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS) as well as neuroprotective
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In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS) as well as neuroprotective effect against glutamate-stimulated neurotoxicity in mouse hippocampal HT22 cells. TMC-256C1 was shown to develop a cellular resistance to oxidative damage caused by glutamate-induced cytotoxicity and reactive oxygen species (ROS) generation in HT22 cells, and suppress the inflammation process in LPS-stimulated BV2 cells. Furthermore, the neuroprotective and anti-neuroinflammatory activities of TMC-256C1 were associated with upregulated expression of heme oxygenase (HO)-1 and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) in HT22 and BV2 cells. We also found that TMC-256C1 activated p38 mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in HT22 and BV2 cells. These results demonstrated that TMC-256C1 activates HO-1 protein expression, probably by increasing nuclear Nrf2 levels via the activation of the p38 MAPK and PI3K/Akt pathways. Full article
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Open AccessReview Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review
Int. J. Mol. Sci. 2016, 17(4), 497; https://doi.org/10.3390/ijms17040497
Received: 18 January 2016 / Revised: 8 March 2016 / Accepted: 28 March 2016 / Published: 2 April 2016
Cited by 25 | PDF Full-text (836 KB) | HTML Full-text | XML Full-text
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red
[...] Read more.
Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials. Full article
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Open AccessArticle Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients
Int. J. Mol. Sci. 2016, 17(4), 463; https://doi.org/10.3390/ijms17040463
Received: 31 December 2015 / Revised: 10 March 2016 / Accepted: 23 March 2016 / Published: 30 March 2016
Cited by 5 | PDF Full-text (774 KB) | HTML Full-text | XML Full-text
Abstract
Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a
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Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34+ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients. Full article
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Open AccessArticle Long-Term Treatment with Citicoline Prevents Cognitive Decline and Predicts a Better Quality of Life after a First Ischemic Stroke
Int. J. Mol. Sci. 2016, 17(3), 390; https://doi.org/10.3390/ijms17030390
Received: 21 January 2016 / Revised: 4 March 2016 / Accepted: 7 March 2016 / Published: 16 March 2016
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Abstract
Stroke, as the leading cause of physical disability and cognitive impairment, has a very significant impact on patients’ quality of life (QoL). The objective of this study is to know the effect of citicoline treatment in Qol and cognitive performance in the long-term
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Stroke, as the leading cause of physical disability and cognitive impairment, has a very significant impact on patients’ quality of life (QoL). The objective of this study is to know the effect of citicoline treatment in Qol and cognitive performance in the long-term in patients with a first ischemic stroke. This is an open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a first ischemic stroke and randomized into parallel arms. Neuropsychological evaluation was performed at 1 month, 6 months, 1 year and 2 years after stroke, and QoL was measured using the EuroQoL-5D questionnaire at 2 years. 163 patients were followed during 2 years. The mean age was 67.5 years-old, and 50.9% were women. Age and absence of citicoline treatment were independent predictors of both utility and poor quality of life. Patients with cognitive impairment had a poorer QoL at 2 years (0.55 vs. 0.66 in utility, p = 0.015). Citicoline treatment improved significantly cognitive status during follow-up (p = 0.005). In conclusion, treatment with long-term citicoline is associated with a better QoL and improves cognitive status 2 years after a first ischemic stroke. Full article
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Open AccessArticle Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology
Int. J. Mol. Sci. 2016, 17(3), 365; https://doi.org/10.3390/ijms17030365
Received: 30 December 2015 / Revised: 2 March 2016 / Accepted: 3 March 2016 / Published: 11 March 2016
Cited by 5 | PDF Full-text (939 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between
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Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related. Full article
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Open AccessReview Chemical Conditioning as an Approach to Ischemic Stroke Tolerance: Mitochondria as the Target
Int. J. Mol. Sci. 2016, 17(3), 351; https://doi.org/10.3390/ijms17030351
Received: 11 February 2016 / Revised: 26 February 2016 / Accepted: 4 March 2016 / Published: 8 March 2016
Cited by 10 | PDF Full-text (1926 KB) | HTML Full-text | XML Full-text
Abstract
It is well established that the brain can be prepared to resist or tolerate ischemic stroke injury, and mitochondrion is a major target for this tolerance. The preparation of ischemic stroke tolerance can be achieved by three major approaches: ischemic conditioning, hypoxic conditioning
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It is well established that the brain can be prepared to resist or tolerate ischemic stroke injury, and mitochondrion is a major target for this tolerance. The preparation of ischemic stroke tolerance can be achieved by three major approaches: ischemic conditioning, hypoxic conditioning and chemical conditioning. In each conditioning approach, there are often two strategies that can be used to achieve the conditioning effects, namely preconditioning (Pre-C) and postconditioning (Post-C). In this review, we focus on chemical conditioning of mitochondrial proteins as targets for neuroprotection against ischemic stroke injury. Mitochondrial targets covered include complexes I, II, IV, the ATP-sensitive potassium channel (mitoKATP), adenine dinucleotide translocase (ANT) and the mitochondrial permeability transition pore (mPTP). While numerous mitochondrial proteins have not been evaluated in the context of chemical conditioning and ischemic stroke tolerance, the paradigms and approaches reviewed in this article should provide general guidelines on testing those mitochondrial components that have not been investigated. A deep understanding of mitochondria as the target of chemical conditioning for ischemic stroke tolerance should provide valuable insights into strategies for fighting ischemic stroke, a leading cause of death in the world. Full article
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Open AccessArticle GLP-2 Attenuates LPS-Induced Inflammation in BV-2 Cells by Inhibiting ERK1/2, JNK1/2 and NF-κB Signaling Pathways
Int. J. Mol. Sci. 2016, 17(2), 190; https://doi.org/10.3390/ijms17020190
Received: 18 December 2015 / Revised: 22 January 2016 / Accepted: 28 January 2016 / Published: 4 February 2016
Cited by 9 | PDF Full-text (2964 KB) | HTML Full-text | XML Full-text
Abstract
The pathogenesis of Parkinson’s disease (PD) often involves the over-activation of microglia. Over-activated microglia could produce several inflammatory mediators, which trigger excessive inflammation and ultimately cause dopaminergic neuron damage. Anti-inflammatory effects of glucagon-like peptide-2 (GLP-2) in the periphery have been shown. Nonetheless, it
[...] Read more.
The pathogenesis of Parkinson’s disease (PD) often involves the over-activation of microglia. Over-activated microglia could produce several inflammatory mediators, which trigger excessive inflammation and ultimately cause dopaminergic neuron damage. Anti-inflammatory effects of glucagon-like peptide-2 (GLP-2) in the periphery have been shown. Nonetheless, it has not been illustrated in the brain. Thus, in this study, we aimed to understand the role of GLP-2 in microglia activation and to elucidate the underlying mechanisms. BV-2 cells were pretreated with GLP-2 and then stimulated by lipopolysaccharide (LPS). Cells were assessed for the responses of pro-inflammatory enzymes (iNOS and COX-2) and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α); the related signaling pathways were evaluated by Western blotting. The rescue effect of GLP-2 on microglia-mediated neurotoxicity was also examined. The results showed that GLP-2 significantly reduced LPS-induced production of inducible nitric oxide synthase (iNOS), cyclooxygenase-s (COX-2), IL-1β, IL-6 and TNF-α. Blocking of Gαs by NF449 resulted in a loss of this anti-inflammatory effect in BV-2 cells. Analyses in signaling pathways demonstrated that GLP-2 reduced LPS-induced phosphorylation of ERK1/2, JNK1/2 and p65, while no effect was observed on p38 phosphorylation. In addition, GLP-2 could suppress microglia-mediated neurotoxicity. All results imply that GLP-2 inhibits LPS-induced microglia activation by collectively regulating ERK1/2, JNK1/2 and p65. Full article
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Open AccessArticle Ginsenoside-Rd Promotes Neurite Outgrowth of PC12 Cells through MAPK/ERK- and PI3K/AKT-Dependent Pathways
Int. J. Mol. Sci. 2016, 17(2), 177; https://doi.org/10.3390/ijms17020177
Received: 28 December 2015 / Revised: 12 January 2016 / Accepted: 22 January 2016 / Published: 29 January 2016
Cited by 9 | PDF Full-text (7281 KB) | HTML Full-text | XML Full-text
Abstract
Panax ginseng is a famous herbal medicine widely used in Asia. Ginsenosides have been identified as the principle active ingredients for Panax ginseng’s biological activity, among which ginsenoside Rd (Rd) attracts extensive attention for its obvious neuroprotective activities. Here we investigated the
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Panax ginseng is a famous herbal medicine widely used in Asia. Ginsenosides have been identified as the principle active ingredients for Panax ginseng’s biological activity, among which ginsenoside Rd (Rd) attracts extensive attention for its obvious neuroprotective activities. Here we investigated the effect of Rd on neurite outgrowth, a crucial process associated with neuronal repair. PC12 cells, which respond to nerve growth factor (NGF) and serve as a model for neuronal cells, were treated with different concentrations of Rd, and then their neurite outgrowth was evaluated. Our results showed that 10 μM Rd significantly increased the percentages of long neurite- and branching neurite-bearing cells, compared with respective controls. The length of the longest neurites and the total length of neurites in Rd-treated PC12 cells were much longer than that of respective controls. We also showed that Rd activated ERK1/2 and AKT but not PKC signalings, and inhibition of ERK1/2 by PD98059 or/and AKT by LY294002 effectively attenuated Rd-induced neurite outgrowth. Moreover, Rd upregulated the expression of GAP-43, a neuron-specific protein involved in neurite outgrowth, while PD98059 or/and LY294002 decreased Rd-induced increased GAP-43 expression. Taken together, our results provided the first evidence that Rd may promote the neurite outgrowth of PC12 cells by upregulating GAP-43 expression via ERK- and ARK-dependent signaling pathways. Full article
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Open AccessArticle Mitochondria Related Pathway Is Essential for Polysaccharides Purified from Sparassis crispa Mediated Neuro-Protection against Glutamate-Induced Toxicity in Differentiated PC12 Cells
Int. J. Mol. Sci. 2016, 17(2), 133; https://doi.org/10.3390/ijms17020133
Received: 30 October 2015 / Revised: 31 December 2015 / Accepted: 12 January 2016 / Published: 26 January 2016
Cited by 10 | PDF Full-text (6955 KB) | HTML Full-text | XML Full-text
Abstract
The present study aims to explore the neuro-protective effects of purified Sparassis crispa polysaccharides against l-glutamic acid (l-Glu)-induced differentiated PC12 (DPC12) cell damages and its underlying mechanisms. The Sparassis crispa water extract was purified by a DEAE-52 cellulose anion exchange
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The present study aims to explore the neuro-protective effects of purified Sparassis crispa polysaccharides against l-glutamic acid (l-Glu)-induced differentiated PC12 (DPC12) cell damages and its underlying mechanisms. The Sparassis crispa water extract was purified by a DEAE-52 cellulose anion exchange column and a Sepharose G-100 column. A fraction with a molecular weight of 75 kDa and a diameter of 88.9 nm, entitled SCWEA, was obtained. SCWEA was identified with a triple helix with (1→3)-linked Rha in the backbone, and (1→2) linkages and (1→6) linkages in the side bone. Our results indicated that the pre-treatment of DPC12 cells with SCWEA prior to l-Glu exposure effectively reversed the reduction on cell viability (by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay) and reduced l-Glu-induced apoptosis (by Hoechst staining). SCWEA decreased the accumulation of intracellular reactive oxygen species, blocked Ca2+ influx and prevented depolarization of the mitochondrial membrane potential in DPC12 cells. Furthermore, SCWEA normalized expression of anti-apoptotic proteins in l-Glu-explored DPC12 cells. These results suggested that SCWEA protects against l-Glu-induced neuronal apoptosis in DPC12 cells and may be a promising candidate for treatment against neurodegenerative disease. Full article
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Open AccessArticle Genipin Derivatives Protect RGC-5 from Sodium Nitroprusside-Induced Nitrosative Stress
Int. J. Mol. Sci. 2016, 17(1), 117; https://doi.org/10.3390/ijms17010117
Received: 20 October 2015 / Revised: 26 November 2015 / Accepted: 8 January 2016 / Published: 19 January 2016
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Abstract
CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5
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CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5 with 750 μM of sodium nitroprusside (SNP) produces nitrosative stress. Both genipin derivatives, however, protect these cells against SNP-induced apoptic cell death, although CHR21 is significantly more potent than CHR20 in this regard. With Western blotting we showed that the observed neuroprotection is primarily due to the activation of protein kinase B (Akt)/eNOS and extracellular signal-regulated kinase (ERK1/2) signaling pathways. Therefore, LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or PD98059 (a MAPK-activating enzyme inhibitor) abrogated the protective effects of CHR20 and CHR21. Altogether, our results show that in our experimental setup neuroprotection by the diasteromeric pair is mediated through the PI3K/Akt/eNOS and ERK1/2 signaling pathways. Further studies are needed to establish the potential of these compounds to prevent ntric oxide (NO)-induced toxicity commonly seen in many neurodegenerative diseases. Full article
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Open AccessReview Retinal Cell Degeneration in Animal Models
Int. J. Mol. Sci. 2016, 17(1), 110; https://doi.org/10.3390/ijms17010110
Received: 23 October 2015 / Revised: 25 December 2015 / Accepted: 8 January 2016 / Published: 15 January 2016
Cited by 7 | PDF Full-text (1207 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient
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The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient retinal ischemia-induced). The target regions, pathology and proposed mechanism of each model are described in a comparative fashion. Animal models of retinal cell degeneration provide insight into the underlying mechanisms of the disease, and will facilitate the development of novel effective therapeutic drugs to treat retinal cell damage. Full article
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Open AccessArticle In Vitro and in Vivo Neuroprotective Effects of Walnut (Juglandis Semen) in Models of Parkinson’s Disease
Int. J. Mol. Sci. 2016, 17(1), 108; https://doi.org/10.3390/ijms17010108
Received: 1 October 2015 / Revised: 31 December 2015 / Accepted: 5 January 2016 / Published: 15 January 2016
Cited by 6 | PDF Full-text (2172 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines including dopamine (DA). MAO expression is elevated in Parkinson’s disease (PD). An increase in MAO activity is closely related to age, and this may induce neuronal degeneration in the brain due to oxidative stress.
[...] Read more.
Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines including dopamine (DA). MAO expression is elevated in Parkinson’s disease (PD). An increase in MAO activity is closely related to age, and this may induce neuronal degeneration in the brain due to oxidative stress. MAO (and particularly monoamine oxidase B (MAO-B)) participates in the generation of reactive oxygen species (ROS), such as hydrogen peroxide that are toxic to dopaminergic cells and their surroundings. Although the polyphenol-rich aqueous walnut extract (JSE; an extract of Juglandis Semen) has been shown to have various beneficial bioactivities, no study has been dedicated to see if JSE is capable to protect dopaminergic neurons against neurotoxic insults in models of PD. In the present study we investigated the neuroprotective potential of JSE against 1-methyl-4-phenylpyridinium (MPP+)- or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicities in primary mesencephalic cells and in a mouse model of PD. Here we show that JSE treatment suppressed ROS and nitric oxide productions triggered by MPP+ in primary mesencephalic cells. JSE also inhibited depletion of striatal DA and its metabolites in vivo that resulted in significant improvement in PD-like movement impairment. Altogether our results indicate that JSE has neuroprotective effects in PD models and may have potential for the prevention or treatment of PD. Full article
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Open AccessReview The Importance of Thrombin in Cerebral Injury and Disease
Int. J. Mol. Sci. 2016, 17(1), 84; https://doi.org/10.3390/ijms17010084
Received: 23 November 2015 / Revised: 28 December 2015 / Accepted: 30 December 2015 / Published: 11 January 2016
Cited by 15 | PDF Full-text (1493 KB) | HTML Full-text | XML Full-text
Abstract
There is increasing evidence that prothrombin and its active derivative thrombin are expressed locally in the central nervous system. So far, little is known about the physiological and pathophysiological functions exerted by thrombin in the human brain. Extra-hepatic prothrombin expression has been identified
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There is increasing evidence that prothrombin and its active derivative thrombin are expressed locally in the central nervous system. So far, little is known about the physiological and pathophysiological functions exerted by thrombin in the human brain. Extra-hepatic prothrombin expression has been identified in neuronal cells and astrocytes via mRNA measurement. The actual amount of brain derived prothrombin is expected to be 1% or less compared to that in the liver. The role in brain injury depends upon its concentration, as higher amounts cause neuroinflammation and apoptosis, while lower concentrations might even be cytoprotective. Its involvement in numerous diseases like Alzheimer’s, multiple sclerosis, cerebral ischemia and haemorrhage is becoming increasingly clear. This review focuses on elucidation of the cerebral thrombin expression, local generation and its role in injury and disease of the central nervous system. Full article
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Open AccessArticle The Anti-Inflammatory Compound Curcumin Enhances Locomotor and Sensory Recovery after Spinal Cord Injury in Rats by Immunomodulation
Int. J. Mol. Sci. 2016, 17(1), 49; https://doi.org/10.3390/ijms17010049
Received: 11 November 2015 / Revised: 23 December 2015 / Accepted: 23 December 2015 / Published: 31 December 2015
Cited by 11 | PDF Full-text (2388 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Well known for its anti-oxidative and anti-inflammation properties, curcumin is a polyphenol found in the rhizome of Curcuma longa. In this study, we evaluated the effects of curcumin on behavioral recovery, glial scar formation, tissue preservation, axonal sprouting, and inflammation after spinal
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Well known for its anti-oxidative and anti-inflammation properties, curcumin is a polyphenol found in the rhizome of Curcuma longa. In this study, we evaluated the effects of curcumin on behavioral recovery, glial scar formation, tissue preservation, axonal sprouting, and inflammation after spinal cord injury (SCI) in male Wistar rats. The rats were randomized into two groups following a balloon compression injury at the level of T9–T10 of the spinal cord, namely vehicle- or curcumin-treated. Curcumin was applied locally on the surface of the injured spinal cord immediately following injury and then given intraperitoneally daily; the control rats were treated with vehicle in the same manner. Curcumin treatment improved behavioral recovery within the first week following SCI as evidenced by improved Basso, Beattie, and Bresnahan (BBB) test and plantar scores, representing locomotor and sensory performance, respectively. Furthermore, curcumin treatment decreased glial scar formation by decreasing the levels of MIP1α, IL-2, and RANTES production and by decreasing NF-κB activity. These results, therefore, demonstrate that curcumin has a profound anti-inflammatory therapeutic potential in the treatment of spinal cord injury, especially when given immediately after the injury. Full article
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Open AccessArticle Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures
Int. J. Mol. Sci. 2016, 17(1), 25; https://doi.org/10.3390/ijms17010025
Received: 1 July 2015 / Revised: 13 November 2015 / Accepted: 18 December 2015 / Published: 28 December 2015
Cited by 13 | PDF Full-text (3199 KB) | HTML Full-text | XML Full-text
Abstract
Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures
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Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation. Full article
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Open AccessCase Report Brain Recovery after a Plane Crash: Treatment with Growth Hormone (GH) and Neurorehabilitation: A Case Report
Int. J. Mol. Sci. 2015, 16(12), 30470-30482; https://doi.org/10.3390/ijms161226244
Received: 28 November 2015 / Revised: 12 December 2015 / Accepted: 16 December 2015 / Published: 21 December 2015
Cited by 11 | PDF Full-text (2011 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study is to describe the results obtained after growth hormone (GH) treatment and neurorehabilitation in a young man that suffered a very grave traumatic brain injury (TBI) after a plane crash. Methods: Fifteen months after the accident, the patient
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The aim of this study is to describe the results obtained after growth hormone (GH) treatment and neurorehabilitation in a young man that suffered a very grave traumatic brain injury (TBI) after a plane crash. Methods: Fifteen months after the accident, the patient was treated with GH, 1 mg/day, at three-month intervals, followed by one-month resting, together with daily neurorehabilitation. Blood analysis at admission showed that no pituitary deficits existed. At admission, the patient presented: spastic tetraplegia, dysarthria, dysphagia, very severe cognitive deficits and joint deformities. Computerized tomography scanners (CT-Scans) revealed the practical loss of the right brain hemisphere and important injuries in the left one. Clinical and blood analysis assessments were performed every three months for three years. Feet surgery was needed because of irreducible equinovarus. Results: Clinical and kinesitherapy assessments revealed a prompt improvement in cognitive functions, dysarthria and dysphagia disappeared and three years later the patient was able to live a practically normal life, walking alone and coming back to his studies. No adverse effects were observed during and after GH administration. Conclusions: These results, together with previous results from our group, indicate that GH treatment is safe and effective for helping neurorehabilitation in TBI patients, once the acute phase is resolved, regardless of whether or not they have GH-deficiency (GHD). Full article
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Open AccessArticle Synthesis and Evaluation of Neuroprotective Selenoflavanones
Int. J. Mol. Sci. 2015, 16(12), 29574-29582; https://doi.org/10.3390/ijms161226188
Received: 1 November 2015 / Revised: 30 November 2015 / Accepted: 4 December 2015 / Published: 10 December 2015
Cited by 1 | PDF Full-text (1239 KB) | HTML Full-text | XML Full-text
Abstract
The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the
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The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the ability to pass through the blood-brain barrier (BBB). They showed in vitro antioxidant effects against hydrogen peroxide, and did not result in severe cytotoxicity. Moreover, infarction volumes in a transient ischemia mouse model were significantly reduced by the selenoflavanone treatments. Full article
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Open AccessReview Cytidine 5′-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives
Int. J. Mol. Sci. 2015, 16(12), 28401-28417; https://doi.org/10.3390/ijms161226099
Received: 31 October 2015 / Revised: 17 November 2015 / Accepted: 19 November 2015 / Published: 30 November 2015
Cited by 4 | PDF Full-text (561 KB) | HTML Full-text | XML Full-text
Abstract
Cytidine 5′-diphosphocholine or citicoline is an endogenous compound that acts in the biosynthetic pathway of phospholipids of cell membranes, particularly phosphatidylcholine, and it is able to increase neurotrasmitters levels in the central nervous system. Citicoline has shown positive effects in Parkinson’s disease and
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Cytidine 5′-diphosphocholine or citicoline is an endogenous compound that acts in the biosynthetic pathway of phospholipids of cell membranes, particularly phosphatidylcholine, and it is able to increase neurotrasmitters levels in the central nervous system. Citicoline has shown positive effects in Parkinson’s disease and Alzheimer’s disease, as well as in amblyopia. Glaucoma is a neurodegenerative disease currently considered a disease involving ocular and visual brain structures. Neuroprotection has been proposed as a valid therapeutic option for those patients progressing despite a well-controlled intraocular pressure, the main risk factor for the progression of the disease. The aim of this review is to critically summarize the current evidence about the effect of citicoline in glaucoma. Full article
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Open AccessArticle Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress
Int. J. Mol. Sci. 2015, 16(12), 28377-28385; https://doi.org/10.3390/ijms161226102
Received: 15 October 2015 / Revised: 18 November 2015 / Accepted: 20 November 2015 / Published: 30 November 2015
Cited by 7 | PDF Full-text (1060 KB) | HTML Full-text | XML Full-text
Abstract
Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present
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Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus. Full article
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Open AccessArticle Transplantation of Human Neural Stem Cells in a Parkinsonian Model Exerts Neuroprotection via Regulation of the Host Microenvironment
Int. J. Mol. Sci. 2015, 16(11), 26473-26492; https://doi.org/10.3390/ijms161125966
Received: 1 August 2015 / Revised: 18 October 2015 / Accepted: 22 October 2015 / Published: 5 November 2015
Cited by 13 | PDF Full-text (14316 KB) | HTML Full-text | XML Full-text
Abstract
Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA) deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs) have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not
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Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA) deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs) have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not well understood. Here, we investigate whether human NSCs (hNSCs) transplantation could provide neuroprotection against DA depletion by recruiting endogenous cells to establish a favorable niche. Adult mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were transplanted with hNSCs or vehicle into the striatum. Behavioral and histological analyses demonstrated significant neurorescue response observed in hNSCs-treated animals compared with the control mice. In transplanted animals, grafted cells survived, proliferated, and migrated within the astrocytic scaffold. Notably, more local astrocytes underwent de-differentiation, acquiring the properties of NSCs or neural precursor cells (NPCs) in mice given hNSCs. Additionally, we also detected significantly higher expression of host-derived growth factors in hNSCs-transplanted mice compared with the control animals, together with inhibition of local microglia and proinflammatory cytokines. Overall, our results indicate that hNSCs transplantation exerts neuroprotection in MPTP-insulted mice via regulating the host niche. Harnessing synergistic interaction between the grafts and host cells may help optimize cell-based therapies for PD. Full article
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Open AccessArticle Roles of Sestrin2 and Ribosomal Protein S6 in Transient Global Ischemia-Induced Hippocampal Neuronal Injury
Int. J. Mol. Sci. 2015, 16(11), 26406-26416; https://doi.org/10.3390/ijms161125963
Received: 16 September 2015 / Revised: 23 October 2015 / Accepted: 23 October 2015 / Published: 4 November 2015
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Abstract
Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex
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Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex that is pivotal for longevity. However, the roles of sestrin2 in cerebral ischemia, in which oxidative stress is one of the major pathogenic mechanisms, are still less understood. In this study, we hypothesized that sestrin2 may protect hippocampal CA1 neurons against transient global ischemia (TGI)-induced apoptosis by regulating RpS6 phosphorylation in rats. We found that sestrin2 expression was progressively increased in the hippocampal CA1 subfield 1–48 h after TGI, reaching the maximal level at 24 h, and declined thereafter. Further, an increased extent of RpS6 phosphorylation, but not total RpS6 protein level, was observed in the hippocampal CA1 subfield after TGI. The sestrin2 siRNA, which substantially blocked the expression of TGI-induced sestrin2, also abolished RpS6 phosphorylation. TGI with reperfusion may induce oxidative stress with the resultant formation of 8-hydroxy-deoxyguanosine (8-OHdG). We found that sestrin2 siRNA further augmented the formation of 8-OHdG induced by TGI with reperfusion for 4 h. Consistently, sestrin2 siRNA also enhanced apoptosis induced by TGI with reperfusion for 48 h based on the analysis of DNA fragmentation by agarose gel electrophoresis, DNA fragmentation sandwich ELISA, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Together these findings indicated that TGI-induced sestrin2 expression contributed to RpS6 phosphorylation and neuroprotection against ischemic injury in the hippocampal CA1 subfield. Full article
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Open AccessReview Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism
Int. J. Mol. Sci. 2015, 16(11), 25959-25981; https://doi.org/10.3390/ijms161125939
Received: 9 June 2015 / Revised: 27 September 2015 / Accepted: 16 October 2015 / Published: 29 October 2015
Cited by 29 | PDF Full-text (1920 KB) | HTML Full-text | XML Full-text
Abstract
Glycogen metabolism has important implications for the functioning of the brain, especially the cooperation between astrocytes and neurons. According to various research data, in a glycogen deficiency (for example during hypoglycemia) glycogen supplies are used to generate lactate, which is then transported to
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Glycogen metabolism has important implications for the functioning of the brain, especially the cooperation between astrocytes and neurons. According to various research data, in a glycogen deficiency (for example during hypoglycemia) glycogen supplies are used to generate lactate, which is then transported to neighboring neurons. Likewise, during periods of intense activity of the nervous system, when the energy demand exceeds supply, astrocyte glycogen is immediately converted to lactate, some of which is transported to the neurons. Thus, glycogen from astrocytes functions as a kind of protection against hypoglycemia, ensuring preservation of neuronal function. The neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported in literature. This review goes on to emphasize that while neurons and astrocytes differ in metabolic profile, they interact to form a common metabolic cooperation. Full article
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Open AccessReview The Potential of Adaptive Design in Animal Studies
Int. J. Mol. Sci. 2015, 16(10), 24048-24058; https://doi.org/10.3390/ijms161024048
Received: 1 September 2015 / Revised: 23 September 2015 / Accepted: 27 September 2015 / Published: 12 October 2015
Cited by 2 | PDF Full-text (638 KB) | HTML Full-text | XML Full-text
Abstract
Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data
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Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research. Full article
Open AccessArticle A Novel Ligustrazine Derivative T-VA Prevents Neurotoxicity in Differentiated PC12 Cells and Protects the Brain against Ischemia Injury in MCAO Rats
Int. J. Mol. Sci. 2015, 16(9), 21759-21774; https://doi.org/10.3390/ijms160921759
Received: 18 June 2015 / Revised: 24 August 2015 / Accepted: 31 August 2015 / Published: 9 September 2015
Cited by 9 | PDF Full-text (6938 KB) | HTML Full-text | XML Full-text
Abstract
Broad-spectrum drugs appear to be more promising for the treatment of acute ischemic stroke. In our previous work, a new ligustrazine derivative (3,5,6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (T-VA) showed neuroprotective effect on injured PC12 cells (EC50 = 4.249 µM). In the current study, we
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Broad-spectrum drugs appear to be more promising for the treatment of acute ischemic stroke. In our previous work, a new ligustrazine derivative (3,5,6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (T-VA) showed neuroprotective effect on injured PC12 cells (EC50 = 4.249 µM). In the current study, we show that this beneficial effect was due to the modulation of nuclear transcription factor-κB/p65 (NF-κB/p65) and cyclooxygenase-2 (COX-2) expressions. We also show that T-VA exhibited neuroprotective effect in a rat model of ischemic stroke with concomitant improvement of motor functions. We propose that the protective effect observed in vivo is owing to increased vascular endothelial growth factor (VEGF) expression, decreased oxidative stress, and up-regulation of Ca2+–Mg2+ ATP enzyme activity. Altogether, our results warrant further studies on the utility of T-VA for the potential treatment of ischemic brain injuries, such as stroke. Full article
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Open AccessReview Evaluation and Management of Neurogenic Bladder: What Is New in China?
Int. J. Mol. Sci. 2015, 16(8), 18580-18600; https://doi.org/10.3390/ijms160818580
Received: 18 June 2015 / Revised: 23 July 2015 / Accepted: 23 July 2015 / Published: 10 August 2015
Cited by 8 | PDF Full-text (2111 KB) | HTML Full-text | XML Full-text
Abstract
Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction (NLUTD), a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves, is a major global medical and social problem. Numerous nervous system abnormalities, such as:
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Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction (NLUTD), a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves, is a major global medical and social problem. Numerous nervous system abnormalities, such as: stroke, Alzheimer’s and Parkinson’s diseases, traumatic spinal cord injury, spinal cord tumors, congenital spina bifida, and diabetes, can cause NB/NLUTD. There are two major types of bladder control problems associated with NB/NLUTD: the bladder becomes either overactive or underactive depending on the nature, level, and extent of nerve damage. This review specifically focuses on the diagnosis and management of NB/NLUTD in China as well as on recent efforts to treat this disease. Full article
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Open AccessReview Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations
Int. J. Mol. Sci. 2015, 16(5), 9772-9793; https://doi.org/10.3390/ijms16059772
Received: 20 January 2015 / Revised: 9 April 2015 / Accepted: 13 April 2015 / Published: 29 April 2015
Cited by 15 | PDF Full-text (1139 KB) | HTML Full-text | XML Full-text
Abstract
Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and
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Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases. Full article
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Open AccessArticle Motor, Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189
Int. J. Mol. Sci. 2015, 16(1), 758-787; https://doi.org/10.3390/ijms16010758
Received: 29 October 2014 / Accepted: 22 December 2014 / Published: 31 December 2014
Cited by 15 | PDF Full-text (6385 KB) | HTML Full-text | XML Full-text
Abstract
We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation,
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We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50–60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI. Full article
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Open AccessArticle Effects of Different Sera Conditions on Olfactory Ensheathing Cells in Vitro
Int. J. Mol. Sci. 2015, 16(1), 420-438; https://doi.org/10.3390/ijms16010420
Received: 24 June 2014 / Accepted: 17 December 2014 / Published: 26 December 2014
Cited by 2 | PDF Full-text (4155 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Transplantation of olfactory ensheathing cells (OEC) is a promising therapy in spinal cord injury (SCI) treatment. However, the therapeutic efficacy of this method is unstable due to unknown reasons. Considering the alterations in the culture environment that occur during OEC preparation for transplantation,
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Transplantation of olfactory ensheathing cells (OEC) is a promising therapy in spinal cord injury (SCI) treatment. However, the therapeutic efficacy of this method is unstable due to unknown reasons. Considering the alterations in the culture environment that occur during OEC preparation for transplantation, we hypothesize that these changes may cause variations in the curative effects of this method. In this study, we compared OEC cultured in medium containing different types and concentrations of serum. After purification and passage, the OEC were cultured for 7 days in different media containing 5%, 10%, 15% or 20% fetal bovine serum (FBS) or rat serum (RS), or the cells were cultured in FBS-containing medium first, followed by medium containing RS. In another group, the OEC were first cultured in 10% FBS for 3 days and then cultured with rat spinal cord explants with 10% RS for another 4 days. An MTT assay and P75 neurotrophin receptor immunofluorescence staining were used to examine cell viability and OEC numbers, respectively. The concentration of neurotrophin-3 (NT-3), which is secreted by OEC into the culture supernatant, was detected using the enzyme-linked immunosorbent assay (ELISA). RT-PCR was applied to investigate the NT-3 gene expression in OEC according to different groups. Compared with FBS, RS reduced OEC proliferation in relation to OEC counts (χ2 = 166.279, df = 1, p < 0.01), the optical density (OD) value in the MTT assay (χ2 = 34.730, df = 1, p < 0.01), and NT-3 concentration in the supernatant (χ2 = 242.997, df = 1, p < 0.01). OEC cultured with spinal cord explants secreted less NT-3 than OEC cultured alone (F = 9.611, df = 5.139, p < 0.01). Meanwhile, the order of application of different sera was not influential. There was statistically significant difference in NT-3 gene expression among different groups when the serum concentration was 15% (χ2 = 64.347, df = 1, p < 0.01). In conclusion, different serum conditions may be responsible for the variations in OEC proliferation and function. Full article
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Open AccessArticle TGF-β1 Protection against Aβ1–42-Induced Neuroinflammation and Neurodegeneration in Rats
Int. J. Mol. Sci. 2014, 15(12), 22092-22108; https://doi.org/10.3390/ijms151222092
Received: 15 August 2014 / Revised: 31 October 2014 / Accepted: 14 November 2014 / Published: 1 December 2014
Cited by 20 | PDF Full-text (2366 KB) | HTML Full-text | XML Full-text
Abstract
Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the
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Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV) in AD model rats, by Aβ1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation. Full article
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Open AccessArticle Sterols from Mytilidae Show Anti-Aging and Neuroprotective Effects via Anti-Oxidative Activity
Int. J. Mol. Sci. 2014, 15(12), 21660-21673; https://doi.org/10.3390/ijms151221660
Received: 31 July 2014 / Revised: 23 October 2014 / Accepted: 3 November 2014 / Published: 25 November 2014
Cited by 10 | PDF Full-text (5241 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
For screening anti-aging samples from marine natural products, K6001 yeast strain was employed as a bioassay system. The active mussel extract was separated to give an active sterol fraction (SF). SF was further purified, and four sterol compounds were obtained. Their structures were
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For screening anti-aging samples from marine natural products, K6001 yeast strain was employed as a bioassay system. The active mussel extract was separated to give an active sterol fraction (SF). SF was further purified, and four sterol compounds were obtained. Their structures were determined to be cholesterol (CHOL), brassicasterol, crinosterol, and 24-methylenecholesterol. All compounds showed similar anti-aging activity. To understand the action mechanism involved, anti-oxidative experiments, reactive oxygen species (ROS) assays, and malondialdehyde (MDA) tests were performed on the most abundant compound, CHOL. Results indicated that treatment with CHOL increases the survival rate of yeast under oxidative stress and decreases ROS and MDA levels. In addition, mutations of uth1, skn7, sod1, and sod2, which feature a K6001 background, were employed and the lifespans of the mutations were not affected by CHOL. These results demonstrate that CHOL exerts anti-aging effects via anti-oxidative stress. Based on the connection between neuroprotection and anti-aging, neuroprotective experiments were performed in PC12 cells. Paraquat was used to induce oxidative stress and the results showed that the CHOL and SF protect the PC12 cells from the injury induced by paraquat. In addition, these substance exhibited nerve growth factor (NGF) mimic activities again confirmed their neuroprotective function. Full article
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