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Special Issue "Pathology and Treatment of Central Nervous System Diseases"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 November 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Cesar Borlongan (Website)

Department of Neurosurgery, MDC 78, University of South Florida College Medicine, Tampa, FL 33612, USA
Interests: stem cell therapy; stroke, neonatal hypoxic-ischemic injury; Parkinson's disease; traumatic brain injury; translational research
Co-Guest Editor
Dr. Kazutaka Shinozuka

Department of Neurosurgery, MDC 78, University of South Florida College Medicine, Tampa, FL 33612, USA

Special Issue Information

Dear Colleagues,

This special issue of the International Journal of Molecular Sciences is dedicated to research papers and review articles on our understanding of novel pathologic findings in central nervous system (CNS) diseases and their treatment.  We recognize that this research theme covers a wide range of CNS disorders ranging from acute (stroke and traumatic brain injury) to chronic (neurodegenerative such as Parkinson’s disease, Alzheimer’s disease), but highlight the underlying pathological manifestations of each disorder.  We encourage authors to provide insights on future therapeutic targets that will abrogate these CNS disorders with emphasis on altering the pathologic symptoms. We envision that with this strategy of elucidating novel pathological observations associated with the CNS disease, one will gain a much deeper appreciation of the mechanisms of cell death, as well as to begin to advance innovative treatment interventions designed to arrest the early, subacute, and late phases of the disease onset and progression.  The objective of this special issue is to bring together basic scientists, translational researchers, and clinicians who are major proponents of understanding and treating the pathologic brain environment after injury.

Prof. Dr. Cesar Borlongan
Dr. Kazutaka Shinozuka
Guest Editors

Submission

Manuscripts should 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. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.

Keywords

  • brain disorders
  • cell death
  • therapeutic intervention
  • mechanisms
  • translational
  • stroke
  • traumatic brain injury
  • Parkinson’s disease
  • Alzheimer’s disease
  • Epilepsy
  • Huntington’s disease

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessArticle Non-Specific Inhibition of Ischemia- and Acidosis-Induced Intracellular Calcium Elevations and Membrane Currents by α-Phenyl-N-tert-butylnitrone, Butylated Hydroxytoluene and Trolox
Int. J. Mol. Sci. 2014, 15(3), 3596-3611; doi:10.3390/ijms15033596
Received: 29 November 2013 / Revised: 29 January 2014 / Accepted: 17 February 2014 / Published: 27 February 2014
Cited by 1 | PDF Full-text (1067 KB) | HTML Full-text | XML Full-text
Abstract
Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce [...] Read more.
Ischemia, and subsequent acidosis, induces neuronal death following brain injury. Oxidative stress is believed to be a key component of this neuronal degeneration. Acute chemical ischemia (azide in the absence of external glucose) and acidosis (external media buffered to pH 6.0) produce increases in intracellular calcium concentration ([Ca2+]i) and inward membrane currents in cultured rat cortical neurons. Two α-tocopherol analogues, trolox and butylated hydroxytoluene (BHT), and the spin trapping molecule α-Phenyl-N-tert-butylnitrone (PBN) were used to determine the role of free radicals in these responses. PBN and BHT inhibited the initial transient increases in [Ca2+]i, produced by ischemia, acidosis and acidic ischemia and increased steady state levels in response to acidosis and the acidic ischemia. BHT and PBN also potentiated the rate at which [Ca2+]i increased after the initial transients during acidic ischemia. Trolox inhibited peak and sustained increases in [Ca2+]i during ischemia. BHT inhibited ischemia induced initial inward currents and trolox inhibited initial inward currents activated by acidosis and acidic ischemia. Given the inconsistent results obtained using these antioxidants, it is unlikely their effects were due to elimination of free radicals. Instead, it appears these compounds have non-specific effects on the ion channels and exchangers responsible for these responses. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessCommunication Luteolin Reduces Alzheimer’s Disease Pathologies Induced by Traumatic Brain Injury
Int. J. Mol. Sci. 2014, 15(1), 895-904; doi:10.3390/ijms15010895
Received: 29 October 2013 / Revised: 3 January 2014 / Accepted: 6 January 2014 / Published: 9 January 2014
Cited by 12 | PDF Full-text (357 KB) | HTML Full-text | XML Full-text
Abstract
Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting [...] Read more.
Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessArticle Combination BMSC and Niaspan Treatment of Stroke Enhances White Matter Remodeling and Synaptic Protein Expression in Diabetic Rats
Int. J. Mol. Sci. 2013, 14(11), 22221-22232; doi:10.3390/ijms141122221
Received: 1 August 2013 / Revised: 16 October 2013 / Accepted: 18 October 2013 / Published: 11 November 2013
Cited by 6 | PDF Full-text (1266 KB) | HTML Full-text | XML Full-text
Abstract
Objective: White matter remodeling plays an important role in neurological recovery after stroke. Bone marrow stromal cells (BMSCs) and Niaspan, an agent which increases high density lipoprotein (HDL), each induces neurorestorative effects and promotes white matter remodeling after stroke in non-diabetic rats. [...] Read more.
Objective: White matter remodeling plays an important role in neurological recovery after stroke. Bone marrow stromal cells (BMSCs) and Niaspan, an agent which increases high density lipoprotein (HDL), each induces neurorestorative effects and promotes white matter remodeling after stroke in non-diabetic rats. In this study, we test whether combination of BMSCs with Niaspan induces an enhanced white matter remodeling in the ischemic brain of diabetic rats. Research design and methods: Type-1 diabetes (T1DM) rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated with or without BMSCs; Niaspan; and the combination of BMSCs + Niaspan daily for 14 days after MCAo. Immunostaining for white matter remodeling and synaptic protein expression including NG2; CNPase; BS (Bielschowsky silver); LFB (luxol fast blue); Synaptophysin and SMI-31 immunostaining were performed. Results: BMSC monotherapy did not regulate NG2 and CNPase expression compared to T1DM control rats. Both, combination of BMSCs + Niaspan treatment, and Niaspan monotherapy significantly increase NG2 and CNPase expression compared to T1DM control. While combination BMSC+Niaspan, BMSC monotherapy and Niaspan monotherapy groups all increase BS, LFB, synaptophysin, and SMI-31 expression in the ischemic brain compared to T1DM-MCAo control. In addition, the combination treatment significantly enhances LFB, SMI-31, and Synaptophysin expression compared to BMSC monotherapy. Conclusions: Combination treatment of stroke with BMSCs and Niaspan in T1DM rats increases white matter remodeling and additively increases BMSC monotherapy induced myelination and synaptic plasticity after stroke in T1DM rats. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessArticle Neuroprotective Effects of Liraglutide for Stroke Model of Rats
Int. J. Mol. Sci. 2013, 14(11), 21513-21524; doi:10.3390/ijms141121513
Received: 2 September 2013 / Revised: 18 October 2013 / Accepted: 23 October 2013 / Published: 30 October 2013
Cited by 24 | PDF Full-text (324 KB) | HTML Full-text | XML Full-text
Abstract
The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke [...] Read more.
The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson’s test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessArticle Crosstalk between Delta Opioid Receptor and Nerve Growth Factor Signaling Modulates Neuroprotection and Differentiation in Rodent Cell Models
Int. J. Mol. Sci. 2013, 14(10), 21114-21139; doi:10.3390/ijms141021114
Received: 15 August 2013 / Revised: 16 September 2013 / Accepted: 26 September 2013 / Published: 21 October 2013
Cited by 4 | PDF Full-text (1185 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Both opioid signaling and neurotrophic factor signaling have played an important role in neuroprotection and differentiation in the nervous system. Little is known about whether the crosstalk between these two signaling pathways will affect neuroprotection and differentiation. Previously, we found that nerve [...] Read more.
Both opioid signaling and neurotrophic factor signaling have played an important role in neuroprotection and differentiation in the nervous system. Little is known about whether the crosstalk between these two signaling pathways will affect neuroprotection and differentiation. Previously, we found that nerve growth factor (NGF) could induce expression of the delta opioid receptor gene (Oprd1, dor), mainly through PI3K/Akt/NF-κB signaling in PC12h cells. In this study, using two NGF-responsive rodent cell model systems, PC12h cells and F11 cells, we found the delta opioid neuropeptide [D-Ala2, D-Leu5] enkephalin (DADLE)-mediated neuroprotective effect could be blocked by pharmacological reagents: the delta opioid antagonist naltrindole, PI3K inhibitor LY294002, MAPK inhibitor PD98059, and Trk inhibitor K252a, respectively. Western blot analysis revealed that DADLE activated both the PI3K/Akt and MAPK pathways in the two cell lines. siRNA Oprd1 gene knockdown experiment showed that the upregulation of NGF mRNA level was inhibited with concomitant inhibition of the survival effects of DADLE in the both cell models. siRNA Oprd1 gene knockdown also attenuated the DADLE-mediated neurite outgrowth in PC12h cells as well as phosphorylation of MAPK and Akt in PC12h and F11 cells, respectively. These data together strongly suggest that delta opioid peptide DADLE acts through the NGF-induced functional G protein-coupled Oprd1 to provide its neuroprotective and differentiating effects at least in part by regulating survival and differentiating MAPK and PI3K/Akt signaling pathways in NGF-responsive rodent neuronal cells. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessArticle Presence of proNGF-Sortilin Signaling Complex in Nigral Dopamine Neurons and Its Variation in Relation to Aging, Lactacystin and 6-OHDA Insults
Int. J. Mol. Sci. 2013, 14(7), 14085-14104; doi:10.3390/ijms140714085
Received: 17 May 2013 / Revised: 20 June 2013 / Accepted: 25 June 2013 / Published: 8 July 2013
PDF Full-text (10721 KB) | HTML Full-text | XML Full-text
Abstract
Growing evidence has shown that proNGF-p75NTR-sortilin signaling might be a crucial factor in neurodegeneration, but it remains unclear if it may function in nigral neurons under aging and disease. The purpose of this study is to examine and quantify proNGF and sortilin [...] Read more.
Growing evidence has shown that proNGF-p75NTR-sortilin signaling might be a crucial factor in neurodegeneration, but it remains unclear if it may function in nigral neurons under aging and disease. The purpose of this study is to examine and quantify proNGF and sortilin expression in the substantia nigra and dynamic changes of aging in lactacystin and 6-hydroxydopamine (6-OHDA) rat models of Parkinson’s disease using immunofluorescence, electronic microscopy, western blot and FLIVO staining methods. The expression of proNGF and sortilin was abundantly and selectively identified in tyrosine hydroxylase (TH)-containing dopamine neurons in the substantia nigra. These proNGF/TH, sortilin/TH-positive neurons were densely distributed in the ventral tier, while they were less distributed in the dorsal tier, where calbindin-D28K-containing neurons were numerously located. A correlated decrease of proNGF, sortilin and TH was also detected during animal aging process. While increase of proNGF, sortilin and cleaved (active) caspase-3 expression was found in the lactacystin model, dynamic proNGF and sortilin changes along with dopamine neuronal loss were demonstrated in the substantia nigra of both the lactacystin and 6-OHDA models. This study has thus revealed the presence of the proNGF-sortilin signaling complex in nigral dopamine neurons and its response to aging, lactacystin and 6-OHDA insults, suggesting that it might contribute to neuronal apoptosis or neurodegeneration during pathogenesis and disease progression of Parkinson’s disease; the underlying mechanism and key signaling pathways involved warrant further investigation. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)

Review

Jump to: Research

Open AccessReview Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction
Int. J. Mol. Sci. 2014, 15(3), 4671-4713; doi:10.3390/ijms15034671
Received: 29 November 2013 / Revised: 11 February 2014 / Accepted: 4 March 2014 / Published: 18 March 2014
Cited by 15 | PDF Full-text (1033 KB) | HTML Full-text | XML Full-text
Abstract
Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and [...] Read more.
Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Figures

Open AccessReview The Neuroprotective Role of Acupuncture and Activation of the BDNF Signaling Pathway
Int. J. Mol. Sci. 2014, 15(2), 3234-3252; doi:10.3390/ijms15023234
Received: 28 November 2013 / Revised: 8 February 2014 / Accepted: 10 February 2014 / Published: 21 February 2014
Cited by 10 | PDF Full-text (480 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the [...] Read more.
Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Use of Genetically Modified Mesenchymal Stem Cells to Treat Neurodegenerative Diseases
Int. J. Mol. Sci. 2014, 15(2), 1719-1745; doi:10.3390/ijms15021719
Received: 2 December 2013 / Revised: 18 December 2013 / Accepted: 14 January 2014 / Published: 23 January 2014
Cited by 14 | PDF Full-text (268 KB) | HTML Full-text | XML Full-text
Abstract
The transplantation of mesenchymal stem cells (MSCs) for treating neurodegenerative disorders has received growing attention recently because these cells are readily available, easily expanded in culture, and when transplanted, survive for relatively long periods of time. Given that such transplants have been [...] Read more.
The transplantation of mesenchymal stem cells (MSCs) for treating neurodegenerative disorders has received growing attention recently because these cells are readily available, easily expanded in culture, and when transplanted, survive for relatively long periods of time. Given that such transplants have been shown to be safe in a variety of applications, in addition to recent findings that MSCs have useful immunomodulatory and chemotactic properties, the use of these cells as vehicles for delivering or producing beneficial proteins for therapeutic purposes has been the focus of several labs. In our lab, the use of genetic modified MSCs to release neurotrophic factors for the treatment of neurodegenerative diseases is of particular interest. Specifically, glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) have been recognized as therapeutic trophic factors for Parkinson’s, Alzheimer’s and Huntington’s diseases, respectively. The aim of this literature review is to provide insights into: (1) the inherent properties of MSCs as a platform for neurotrophic factor delivery; (2) the molecular tools available for genetic manipulation of MSCs; (3) the rationale for utilizing various neurotrophic factors for particular neurodegenerative diseases; and (4) the clinical challenges of utilizing genetically modified MSCs. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Traumatic Brain Injury Pathophysiology and Treatments: Early, Intermediate, and Late Phases Post-Injury
Int. J. Mol. Sci. 2014, 15(1), 309-341; doi:10.3390/ijms15010309
Received: 10 November 2013 / Revised: 2 December 2013 / Accepted: 20 December 2013 / Published: 30 December 2013
Cited by 41 | PDF Full-text (375 KB) | HTML Full-text | XML Full-text
Abstract
Traumatic Brain Injury (TBI) affects a large proportion and extensive array of individuals in the population. While precise pathological mechanisms are lacking, the growing base of knowledge concerning TBI has put increased emphasis on its understanding and treatment. Most treatments of TBI [...] Read more.
Traumatic Brain Injury (TBI) affects a large proportion and extensive array of individuals in the population. While precise pathological mechanisms are lacking, the growing base of knowledge concerning TBI has put increased emphasis on its understanding and treatment. Most treatments of TBI are aimed at ameliorating secondary insults arising from the injury; these insults can be characterized with respect to time post-injury, including early, intermediate, and late pathological changes. Early pathological responses are due to energy depletion and cell death secondary to excitotoxicity, the intermediate phase is characterized by neuroinflammation and the late stage by increased susceptibility to seizures and epilepsy. Current treatments of TBI have been tailored to these distinct pathological stages with some overlap. Many prophylactic, pharmacologic, and surgical treatments are used post-TBI to halt the progression of these pathologic reactions. In the present review, we discuss the mechanisms of the pathological hallmarks of TBI and both current and novel treatments which target the respective pathways. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Regenerative Medicine for Epilepsy: From Basic Research to Clinical Application
Int. J. Mol. Sci. 2013, 14(12), 23390-23401; doi:10.3390/ijms141223390
Received: 4 September 2013 / Revised: 31 October 2013 / Accepted: 15 November 2013 / Published: 28 November 2013
Cited by 2 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients [...] Read more.
Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients still suffer from intractable seizures despite the advent of the multimodality of therapies. In this article, we initially provide an overview of clinical presentation of epilepsy then describe clinically relevant animal models of epilepsy. Subsequently, we discuss the concepts of regenerative medicine including cell therapy, neuroprotective agents, and electrical stimulation, which are reviewed within the context of our data. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview New Insights in the Pathogenesis of Multiple Sclerosis—Role of Acrolein in Neuronal and Myelin Damage
Int. J. Mol. Sci. 2013, 14(10), 20037-20047; doi:10.3390/ijms141020037
Received: 13 August 2013 / Revised: 17 September 2013 / Accepted: 18 September 2013 / Published: 9 October 2013
Cited by 10 | PDF Full-text (156 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury [...] Read more.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by an inappropriate inflammatory reaction resulting in widespread myelin injury along white matter tracts. Neurological impairment as a result of the disease can be attributed to immune-mediated injury to myelin, axons and mitochondria, but the molecular mechanisms underlying the neuropathy remain incompletely understood. Incomplete mechanistic knowledge hinders the development of therapies capable of alleviating symptoms and slowing disease progression in the long-term. Recently, oxidative stress has been implicated as a key component of neural tissue damage prompting investigation of reactive oxygen species (ROS) scavengers as a potential therapeutic option. Despite the establishment of oxidative stress as a crucial process in MS development and progression, ROS scavengers have had limited success in animal studies which has prompted pursuit of an alternative target capable of curtailing oxidative stress. Acrolein, a toxic β-unsaturated aldehyde capable of initiating and perpetuating oxidative stress, has been suggested as a viable point of intervention to guide the development of new treatments. Sequestering acrolein using an FDA-approved compound, hydralazine, offers neuroprotection resulting in dampened symptom severity and slowed disease progression in experimental autoimmune encephalomyelitis (EAE) mice. These results provide promise for therapeutic development, indicating the possible utility of neutralizing acrolein to preserve and improve neurological function in MS patients. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke
Int. J. Mol. Sci. 2013, 14(9), 18899-18924; doi:10.3390/ijms140918899
Received: 15 August 2013 / Revised: 7 September 2013 / Accepted: 9 September 2013 / Published: 13 September 2013
Cited by 12 | PDF Full-text (290 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), [...] Read more.
Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Delta Opioid Receptor and Its Peptide: A Receptor-Ligand Neuroprotection
Int. J. Mol. Sci. 2013, 14(9), 17410-17419; doi:10.3390/ijms140917410
Received: 30 July 2013 / Revised: 15 August 2013 / Accepted: 19 August 2013 / Published: 23 August 2013
Cited by 4 | PDF Full-text (411 KB) | HTML Full-text | XML Full-text
Abstract
In pursuit of neurological therapies, the opioid system, specifically delta opioid receptors and delta opioid peptides, demonstrates promising therapeutic potential for stroke, Parkinson’s disease, and other degenerative neurological conditions. Recent studies offer strong evidence in support of the therapeutic use of delta [...] Read more.
In pursuit of neurological therapies, the opioid system, specifically delta opioid receptors and delta opioid peptides, demonstrates promising therapeutic potential for stroke, Parkinson’s disease, and other degenerative neurological conditions. Recent studies offer strong evidence in support of the therapeutic use of delta opioid receptors, and provide insights into the underlying mechanisms of action. Delta opioid receptors have been shown to confer protective effects by mediating ionic homeostasis and activating endogenous neuroprotective pathways. Additionally, delta opioid agonists such as (D-Ala 2, D-Leu 5) enkephalin (DADLE) have been shown to decrease apoptosis and promote neuronal survival. In its entirety, the delta opioid system represents a promising target for neural therapies. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Proteolytic Cleavage of Apolipoprotein E4 as the Keystone for the Heightened Risk Associated with Alzheimer’s Disease
Int. J. Mol. Sci. 2013, 14(7), 14908-14922; doi:10.3390/ijms140714908
Received: 6 June 2013 / Revised: 26 June 2013 / Accepted: 12 July 2013 / Published: 17 July 2013
Cited by 13 | PDF Full-text (2416 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)
Open AccessReview Wharton’s Jelly-Derived Mesenchymal Stem Cells: Phenotypic Characterization and Optimizing Their Therapeutic Potential for Clinical Applications
Int. J. Mol. Sci. 2013, 14(6), 11692-11712; doi:10.3390/ijms140611692
Received: 25 April 2013 / Revised: 22 May 2013 / Accepted: 27 May 2013 / Published: 31 May 2013
Cited by 53 | PDF Full-text (367 KB) | HTML Full-text | XML Full-text
Abstract
Wharton’s jelly (WJ) is a gelatinous tissue within the umbilical cord that contains myofibroblast-like stromal cells. A unique cell population of WJ that has been suggested as displaying the stemness phenotype is the mesenchymal stromal cells (MSCs). Because MSCs’ stemness and immune [...] Read more.
Wharton’s jelly (WJ) is a gelatinous tissue within the umbilical cord that contains myofibroblast-like stromal cells. A unique cell population of WJ that has been suggested as displaying the stemness phenotype is the mesenchymal stromal cells (MSCs). Because MSCs’ stemness and immune properties appear to be more robustly expressed and functional which are more comparable with fetal than adult-derived MSCs, MSCs harvested from the “young” WJ are considered much more proliferative, immunosuppressive, and even therapeutically active stem cells than those isolated from older, adult tissue sources such as the bone marrow or adipose. The present review discusses the phenotypic characteristics, therapeutic applications, and optimization of experimental protocols for WJ-derived stem cells. MSCs derived from WJ display promising transplantable features, including ease of sourcing, in vitro expandability, differentiation abilities, immune-evasion and immune-regulation capacities. Accumulating evidence demonstrates that WJ-derived stem cells possess many potential advantages as transplantable cells for treatment of various diseases (e.g., cancer, chronic liver disease, cardiovascular diseases, nerve, cartilage and tendon injury). Additional studies are warranted to translate the use of WJ-derived stem cells for clinical applications. Full article
(This article belongs to the Special Issue Pathology and Treatment of Central Nervous System Diseases)

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