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Special Issue "Neuroprotective Strategies (special issue)"

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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 (15 August 2010)

Special Issue Editor

Guest Editor
Prof. Dr. Katalin Prokai-Tatrai

Center for Neuroscience Discovery, Department of Pharmaceutical Sciences, University of North Texas; Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
Website | E-Mail
Fax: +1 817 735 2118
Interests: medicinal chemistry: drug design of central nervous system agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; oxidative stress; estrogens and other phenolic antioxidants; protein carbonylationmedicinal chemistry: drug design of central nervous system agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; oxidative stress; estrogens and other phenolic antioxidants; protein carbonylation

Special Issue Information

Dear Colleagues,

This Special Issue is aimed at both the basic science and clinical aspects of neuroprotective approaches to acute (e.g., brain or spinal cord trauma, stroke), and chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases, age-related macular degeneration) diseases. Potential and existing interventions, either as reviews or original papers, to prevent neuronal cell death in the CNS and in the periphery are welcome to this special issue. The concept of neuroprotection in therapeutic terms may be best described by Shouldon (Science, 1998; 282:1072) as "pharmacological interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis and thereby forestalling onset of disease or clinical decline." Our life span has increased and it brought about a significant increase in the incidence of neurodegenerative diseases. While each neurodegenerative disease has its own characteristics and clinical manifestations, some common markers have been recognized. Among others, increased levels of oxidative/nitrosative damage to DNA, RNA, mitochondria, membranes, and proteins, etc. have been detected in connection with situations of neuronal damage. The wide variety of approaches to rescue neurons includes free radical scavenging antioxidants, ion channel modulators, excitatory amino acid antagonists and neurotrophic factors. Stem-cell based approaches may also represent a new opportunity to treat neurodegenerative diseases. I wish to thank all the authors for their contribution to this special issue.

Dr. Katalin Prokai-Tatrai
Guest Editor

Keywords

  • aging
  • Alzheimer's disease
  • amyotrophic lateral sclerosis
  • anti-apoptotic drugs
  • antioxidants
  • apoptosis
  • axon damage
  • bioavailability
  • blood-brain barrier
  • caspases
  • cognition
  • excitotoxicity
  • free radicals
  • GABA agonists
  • glaucoma
  • growth factors
  • hydroxyl radical
  • hypothermia
  • hypoxia
  • inflammation
  • ion channels
  • iron chelators
  • ischemia
  • ischemic optic neuropathy
  • lipid peroxidation
  • MEK/ERK signaling pathway
  • mitochondria
  • necrosis
  • neurogenesis
  • neurotrophic factors
  • nitric oxide synthase
  • nitrosative/oxidative stress
  • NMDA agonist
  • nutraceuticals
  • Parkinson’s disease
  • peripheral neurons
  • peroxinitrite
  • posttranslational modification
  • protein aggregates
  • proteomics
  • redox-active metals
  • retinal ganglion cells
  • spinal cord injury
  • stem cell
  • steroids
  • stroke
  • superoxide dismutase
  • therapeutic window
  • traumatic brain injury

Related Special Issues

Published Papers (18 papers)

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Research

Jump to: Review

Open AccessArticle In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy
Int. J. Mol. Sci. 2011, 12(1), 694-724; doi:10.3390/ijms12010694
Received: 2 December 2010 / Revised: 14 January 2011 / Accepted: 15 January 2011 / Published: 19 January 2011
Cited by 32 | PDF Full-text (1440 KB) | HTML Full-text | XML Full-text
Abstract
The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer’s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing
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The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer’s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer’s disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessArticle Neuroprotective Properties of Picroside II in a Rat Model of Focal Cerebral Ischemia
Int. J. Mol. Sci. 2010, 11(11), 4580-4590; doi:10.3390/ijms11114580
Received: 6 October 2010 / Revised: 30 October 2010 / Accepted: 30 October 2010 / Published: 16 November 2010
Cited by 28 | PDF Full-text (128 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to explore the effect of picroside II on neuronal apoptosis and the expression of caspase-3 and poly ADP-ribose polymerase (PARP) following middle cerebral artery occlusion/reperfusion in male Wistar rats. Picroside II (10 mg/kg) was administered intravenously into
[...] Read more.
The aim of this study was to explore the effect of picroside II on neuronal apoptosis and the expression of caspase-3 and poly ADP-ribose polymerase (PARP) following middle cerebral artery occlusion/reperfusion in male Wistar rats. Picroside II (10 mg/kg) was administered intravenously into the tail vein of the animals. The neurological function deficits were evaluated with the Bederson’s test and the cerebral infarction volume was visualized with tetrazolium chloride (TTC) staining. The apoptotic cells were counted by in situ terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) assay. The immunohistochemistry stain and enzyme linked immunosorbent assay (ELISA) was used to determine the expressions of caspase-3 and PARP in brain tissue. The results indicated that rats in the control group showed neurological function deficit and cerebral infarction in ischemic hemisphere after two hours ischemia followed by 22 hours reperfusion. Caspase-3 and PARP expressions were also profound in the cortex, the striatum and the hippocampus, along with increased apoptotic cells in this group. Bederson's score, infarction volume, and expressions of caspase-3 and PARP, as well as apoptosis in the treatment group were, however, significantly decreased compared to those in the control group indicating that intravenous treatment with picroside II might be beneficial to inhibit neuronal apoptosis and, thus, to improve the neurological function of rats upon cerebral ischemia reperfusion injury. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessArticle Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease
Int. J. Mol. Sci. 2010, 11(11), 4465-4487; doi:10.3390/ijms11114465
Received: 20 September 2010 / Revised: 22 October 2010 / Accepted: 27 October 2010 / Published: 9 November 2010
Cited by 10 | PDF Full-text (1454 KB) | HTML Full-text | XML Full-text
Abstract
Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we
[...] Read more.
Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson’s disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6‑OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle The Effect of Treadmill Training Pre-Exercise on Glutamate Receptor Expression in Rats after Cerebral Ischemia
Int. J. Mol. Sci. 2010, 11(7), 2658-2669; doi:10.3390/ijms11072658
Received: 4 June 2010 / Revised: 2 July 2010 / Accepted: 2 July 2010 / Published: 7 July 2010
Cited by 21 | PDF Full-text (474 KB) | HTML Full-text | XML Full-text
Abstract
Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat
[...] Read more.
Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO). Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation group. After treadmill training, ischemia was induced by occluding the MCA for 2 h, followed by reperfusion. Half of the rats in each group were sacrificed for mRNA detection of mGluR5 and NR2B 80 min after occlusion. The remaining animals were evaluated for neurological deficits by behavioral scoring and then decapitated to assess the infarct volume. The mRNA expression of mGluR5 and NR2B was detected by real-time PCR. The results suggest that pre-ischemic treadmill training may induce brain ischemic tolerance by reducing the mRNA levels of mGluR5 and NR2B, and thus, the results indicate that physical exercise might be an effective method to establish ischemic preconditioning. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle Neuritogenic and Neuroprotective Properties of Peptide Agonists of the Fibroblast Growth Factor Receptor
Int. J. Mol. Sci. 2010, 11(6), 2291-2305; doi:10.3390/ijms11062291
Received: 16 April 2010 / Accepted: 21 May 2010 / Published: 26 May 2010
Cited by 4 | PDF Full-text (323 KB) | HTML Full-text | XML Full-text
Abstract
Fibroblast growth factor receptors (FGFRs) interact with their cognate ligands, FGFs, and with a number of cell adhesion molecules (CAMs), such as the neural cell adhesion molecule (NCAM), mediating a wide range of events during the development and maintenance of the nervous system.
[...] Read more.
Fibroblast growth factor receptors (FGFRs) interact with their cognate ligands, FGFs, and with a number of cell adhesion molecules (CAMs), such as the neural cell adhesion molecule (NCAM), mediating a wide range of events during the development and maintenance of the nervous system. Determination of protein structure, in silico modeling and biological studies have recently resulted in the identification of FGFR binding peptides derived from various FGFs and NCAM mimicking the effects of these molecules with regard to their neuritogenic and neuroprotective properties. This review focuses on recently developed functional peptide agonists of FGFR with possible therapeutic potential. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle Lutein Protects RGC-5 Cells Against Hypoxia and Oxidative Stress
Int. J. Mol. Sci. 2010, 11(5), 2109-2117; doi:10.3390/ijms11052109
Received: 28 March 2010 / Revised: 13 April 2010 / Accepted: 3 May 2010 / Published: 11 May 2010
Cited by 35 | PDF Full-text (772 KB) | HTML Full-text | XML Full-text
Abstract
Retinal ischemia and oxidative stress lead to neuronal death in many ocular pathologies. Recently, we found that lutein, an oxy-carotenoid, protected the inner retina from ischemia/reperfusion injury. However, it is uncertain whether lutein directly protects retinal ganglion cells (RGCs). Here, an in vitro
[...] Read more.
Retinal ischemia and oxidative stress lead to neuronal death in many ocular pathologies. Recently, we found that lutein, an oxy-carotenoid, protected the inner retina from ischemia/reperfusion injury. However, it is uncertain whether lutein directly protects retinal ganglion cells (RGCs). Here, an in vitro model of hypoxia and oxidative stress was used to further investigate the neuroprotective role of lutein in RGCs. Cobalt chloride (CoCl2)and hydrogen peroxide (H2O2) were added to a transformed RGC cell line, RGC-5, to induce chemical hypoxia and oxidative stress, respectively. Either lutein or vehicle was added to cultured cells. A higher cell count was observed in the lutein-treated cells compared with the vehicle-treated cells. Our data from this in vitro model revealed that lutein might protect RGC-5 cells from damage when exposed to either CoCl2-induced chemical hypoxia or H2O2-induced oxidative stress. These results suggest that lutein may play a role as a neuroprotectant. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessArticle A Novel PARP Inhibitor L-2286 in a Rat Model of Impact Acceleration Head Injury: An Immunohistochemical and Behavioral Study
Int. J. Mol. Sci. 2010, 11(4), 1253-1268; doi:10.3390/ijms11041253
Received: 3 November 2009 / Revised: 11 March 2010 / Accepted: 22 March 2010 / Published: 26 March 2010
Cited by 1 | PDF Full-text (932 KB) | HTML Full-text | XML Full-text
Abstract
We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300-350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286
[...] Read more.
We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300-350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286 administered 30 min after injury, and to test the neuroprotective effect at two time points (immediately, and 30 min after injury). The neuroprotective effect of L-2286 was tested using immunohistochemical (amyloid precursor protein and mid-sized mouse anti-neurofilament clone RMO-14.9 antibody) and behavioral tests (beam-balance, open-field and elevated plus maze). At both time-points, a 100 µg/rat dose of i.c.v. L-2286 significantly (p < 0.05) reduced the density of damaged axons in the corticospinal tract and medial longitudinal fascicle compared to controls. In the behavioral tests, treatment 30 min post-injury improved motor function, while the level of anxiety was reduced in both treatment protocols. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle Melatonin and Structurally-Related Compounds Protect Synaptosomal Membranes from Free Radical Damage
Int. J. Mol. Sci. 2010, 11(1), 312-328; doi:10.3390/ijms11010312
Received: 23 December 2009 / Accepted: 15 January 2010 / Published: 21 January 2010
Cited by 22 | PDF Full-text (296 KB) | HTML Full-text | XML Full-text
Abstract
Since biological membranes are composed of lipids and proteins we tested the in vitro antioxidant properties of several indoleamines from the tryptophan metabolic pathway in the pineal gland against oxidative damage to lipids and proteins of synaptosomes isolated from the rat brain. Free
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Since biological membranes are composed of lipids and proteins we tested the in vitro antioxidant properties of several indoleamines from the tryptophan metabolic pathway in the pineal gland against oxidative damage to lipids and proteins of synaptosomes isolated from the rat brain. Free radicals were generated by incubation with 0.1 mM FeCl3, and 0.1 mM ascorbic acid. Levels of malondialdehyde (MDA) plus 4-hydroxyalkenal (4-HDA), and carbonyl content in the proteins were measured as indices of oxidative damage to lipids and proteins, respectively. Pinoline was the most powerful antioxidant evaluated, with melatonin, N-acetylserotonin, 5-hydroxytryptophan, 5-methoxytryptamine, 5-methoxytryptophol, and tryptoline also acting as antioxidants. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle Neuroprotective Effects of Ischemic Preconditioning on Global Brain Ischemia through Up-Regulation of Acid-Sensing Ion Channel 2a
Int. J. Mol. Sci. 2010, 11(1), 140-153; doi:10.3390/ijms11010140
Received: 13 November 2009 / Revised: 4 January 2010 / Accepted: 7 January 2010 / Published: 12 January 2010
Cited by 13 | PDF Full-text (478 KB) | HTML Full-text | XML Full-text
Abstract
Transient forebrain or global ischemia induces cell death in vulnerable CA1 pyramidal neurons. A brief period of ischemia, i.e., ischemic preconditioning, affords CA1 neurons robust protection against a subsequent, more prolonged ischemic challenge. Using the four-vessel occlusion model, we established an ischemic
[...] Read more.
Transient forebrain or global ischemia induces cell death in vulnerable CA1 pyramidal neurons. A brief period of ischemia, i.e., ischemic preconditioning, affords CA1 neurons robust protection against a subsequent, more prolonged ischemic challenge. Using the four-vessel occlusion model, we established an ischemic preconditioning model in which rodents were subjected to 3 min of sublethal ischemia 48 h before a 15 min lethal ischemia. We showed that preconditioning attenuated the ischemia-induced neural cell death and DNA fragmentation in the hippocampal CA1 region. RT-PCR and western blot analysis showed that preconditioning prior to an ischemic insult significantly increased ASIC 2a mRNA and protein expression in comparison to the ischemic insult alone (p < 0.01). These findings implicate a new role of ASIC 2a on endogenous neuroprotection from ischemic insult. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessArticle Oxidative Neurodegeneration Is Prevented by UCP0045037, an Allosteric Modulator for the Reduced Form of DJ-1, a Wild-Type of Familial Parkinson’s Disease-Linked PARK7
Int. J. Mol. Sci. 2009, 10(11), 4789-4804; doi:10.3390/ijms10114789
Received: 17 September 2009 / Revised: 21 October 2009 / Accepted: 2 November 2009 / Published: 5 November 2009
Cited by 6 | PDF Full-text (1065 KB) | HTML Full-text | XML Full-text
Abstract
Although a loss-of-function mutation has been identified in familial Parkinson’s disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1
[...] Read more.
Although a loss-of-function mutation has been identified in familial Parkinson’s disease PARK7, the wild-type of DJ-1 is known to act as an oxidative stress sensor in neuronal cells. Recently, we identified UCP0045037 as a compound that bound to the reduced form of DJ-1 by in silico virtual screening. In this study, we determined the neuroprotective effects of UCP0045037 against focal cerebral ischemia-induced neurodegeneration in rats. Hydrogen peroxide-induced cell death was significantly inhibited by UCP0045037 in both rat mesencephalic dopaminergic neurons and human normal SH-SY5Y cells. In contrast, DJ-1-knockdown SH-SY5Y cells lost the protective activity of UCP0045037. These results suggest that UCP0045037 interacts with endogenous DJ-1 and produces a neuroprotective response. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))

Review

Jump to: Research

Open AccessReview Mechanisms of Estrogens’ Dose-Dependent Neuroprotective and Neurodamaging Effects in Experimental Models of Cerebral Ischemia
Int. J. Mol. Sci. 2011, 12(3), 1533-1562; doi:10.3390/ijms12031533
Received: 17 August 2010 / Revised: 10 February 2011 / Accepted: 22 February 2011 / Published: 25 February 2011
Cited by 29 | PDF Full-text (446 KB) | HTML Full-text | XML Full-text
Abstract
Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental
[...] Read more.
Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens’ actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessReview The Biochemical and Cellular Basis for Nutraceutical Strategies to Attenuate Neurodegeneration in Parkinson’s Disease
Int. J. Mol. Sci. 2011, 12(1), 506-569; doi:10.3390/ijms12010506
Received: 18 November 2010 / Revised: 5 January 2011 / Accepted: 14 January 2011 / Published: 17 January 2011
Cited by 13 | PDF Full-text (979 KB) | HTML Full-text | XML Full-text
Abstract
Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson’s disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc
[...] Read more.
Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson’s disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc dopaminergic (DAergic) neurons and decay of the striatal tract. While genetic mutations or environmental toxins can precipitate pathology, progressive degenerative succession involves a gradual decline in DA neurotransmission/synaptic uptake, impaired oxidative glucose consumption, a rise in striatal lactate and chronic inflammation. Nutraceuticals play a fundamental role in energy metabolism and signaling transduction pathways that control neurotransmission and inflammation. However, the use of nutritional supplements to slow the progression of PD has met with considerable challenge and has thus far proven unsuccessful. This review re-examines precipitating factors and insults involved in PD and how nutraceuticals can affect each of these biological targets. Discussed are disease dynamics (Sections 1 and 2) and natural substances, vitamins and minerals that could impact disease processes (Section 3). Topics include nutritional influences on α-synuclein aggregation, ubiquitin proteasome function, mTOR signaling/lysosomal-autophagy, energy failure, faulty catecholamine trafficking, DA oxidation, synthesis of toxic DA-quinones, o-semiquinones, benzothiazolines, hyperhomocyseinemia, methylation, inflammation and irreversible oxidation of neuromelanin. In summary, it is clear that future research will be required to consider the multi-faceted nature of this disease and re-examine how and why the use of nutritional multi-vitamin-mineral and plant-based combinations could be used to slow the progression of PD, if possible. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessReview Human Umbilical Cord Blood Stem Cells: Rational for Use as a Neuroprotectant in Ischemic Brain Disease
Int. J. Mol. Sci. 2010, 11(9), 3513-3528; doi:10.3390/ijms11093513
Received: 18 August 2010 / Revised: 15 September 2010 / Accepted: 15 September 2010 / Published: 21 September 2010
Cited by 10 | PDF Full-text (283 KB) | HTML Full-text | XML Full-text
Abstract
The use of stem cells for reparative medicine was first proposed more than three decades ago. Hematopoietic stem cells from bone marrow, peripheral blood and human umbilical cord blood (CB) have gained major use for treatment of hematological indications. CB, however, is also
[...] Read more.
The use of stem cells for reparative medicine was first proposed more than three decades ago. Hematopoietic stem cells from bone marrow, peripheral blood and human umbilical cord blood (CB) have gained major use for treatment of hematological indications. CB, however, is also a source of cells capable of differentiating into various non-hematopoietic cell types, including neural cells. Several animal model reports have shown that CB cells may be used for treatment of neurological injuries. This review summarizes the information available on the origin of CB-derived neuronal cells and the mechanisms proposed to explain their action. The potential use of stem/progenitor cells for treatment of ischemic brain injuries is discussed. Issues that remain to be resolved at the present stage of preclinical trials are addressed. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessReview The Yin and Yang of VEGF and PEDF: Multifaceted Neurotrophic Factors and Their Potential in the Treatment of Parkinson’s Disease
Int. J. Mol. Sci. 2010, 11(8), 2875-2900; doi:10.3390/ijms11082875
Received: 24 May 2010 / Revised: 25 July 2010 / Accepted: 30 July 2010 / Published: 5 August 2010
Cited by 13 | PDF Full-text (405 KB) | HTML Full-text | XML Full-text
Abstract
Over the last few decades, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have emerged as multifaceted players in not only the pathogenesis, but potential treatment, of numerous diseases. They activate diverse intracellular signaling cascades known to have extensive crosstalk, and
[...] Read more.
Over the last few decades, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have emerged as multifaceted players in not only the pathogenesis, but potential treatment, of numerous diseases. They activate diverse intracellular signaling cascades known to have extensive crosstalk, and have been best studied for their effects in cardiology and cancer biology. Recent work with the two factors indicates that the activity of one growth factor is often directly related to the action of the other. Their respective neuroprotective effects, in particular, raise important questions regarding the treatment of neurodegenerative disorders, including Parkinson’s disease. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Open AccessReview An Antiapoptotic Neuroprotective Role for Neuroglobin
Int. J. Mol. Sci. 2010, 11(6), 2306-2321; doi:10.3390/ijms11062306
Received: 10 May 2010 / Revised: 24 May 2010 / Accepted: 24 May 2010 / Published: 27 May 2010
Cited by 32 | PDF Full-text (404 KB) | HTML Full-text | XML Full-text
Abstract
Cell death associated with mitochondrial dysfunction is common in acute neurological disorders and in neurodegenerative diseases. Neuronal apoptosis is regulated by multiple proteins, including neuroglobin, a small heme protein of ancient origin. Neuroglobin is found in high concentration in some neurons, and its
[...] Read more.
Cell death associated with mitochondrial dysfunction is common in acute neurological disorders and in neurodegenerative diseases. Neuronal apoptosis is regulated by multiple proteins, including neuroglobin, a small heme protein of ancient origin. Neuroglobin is found in high concentration in some neurons, and its high expression has been shown to promote survival of neurons in vitro and to protect brain from damage by both stroke and Alzheimer’s disease in vivo. Early studies suggested this protective role might arise from the protein’s capacity to bind oxygen or react with nitric oxide. Recent data, however, suggests that neither of these functions is likely to be of physiological significance. Other studies have shown that neuroglobin reacts very rapidly with cytochrome c released from mitochondria during cell death, thus interfering with the intrinsic pathway of apoptosis. Systems level computational modelling suggests that the physiological role of neuroglobin is to reset the trigger level for the post-mitochondrial execution of apoptosis. An understanding of the mechanism of action of neuroglobin might thus provide a rational basis for the design of new drug targets for inhibiting excessive neuronal cell death. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessReview Stem Cell-Based Neuroprotective and Neurorestorative Strategies
Int. J. Mol. Sci. 2010, 11(5), 2039-2055; doi:10.3390/ijms11052039
Received: 23 March 2010 / Revised: 8 April 2010 / Accepted: 18 April 2010 / Published: 5 May 2010
Cited by 12 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from
[...] Read more.
Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells (iPS), reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessReview Novel Neuroprotective Strategies in Ischemic Retinal Lesions
Int. J. Mol. Sci. 2010, 11(2), 544-561; doi:10.3390/ijms11020544
Received: 7 January 2010 / Revised: 27 January 2010 / Accepted: 27 January 2010 / Published: 3 February 2010
Cited by 16 | PDF Full-text (430 KB) | HTML Full-text | XML Full-text
Abstract
Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review
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Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K+ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
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Open AccessReview Ginkgo biloba Extract in Alzheimer’s Disease: From Action Mechanisms to Medical Practice
Int. J. Mol. Sci. 2010, 11(1), 107-123; doi:10.3390/ijms11010107
Received: 4 November 2009 / Revised: 31 December 2009 / Accepted: 1 January 2010 / Published: 8 January 2010
Cited by 45 | PDF Full-text (201 KB) | HTML Full-text | XML Full-text
Abstract
Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements. Numerous preclinical studies have shown the neuroprotective effects of EGb761 and support the notion that it may be effective in the treatment and
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Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements. Numerous preclinical studies have shown the neuroprotective effects of EGb761 and support the notion that it may be effective in the treatment and prevention of neurodegenerative disorders such as Alzheimer’s disease (AD). Despite the preclinical promise, the clinical efficacy of this drug remains elusive. In this review, possible mechanisms underlying neuroprotective actions of EGb761 are described in detail, together with a brief discussion of the problem of studying this herb clinically to verify its efficacy in the treatment and prevention of AD. Moreover, various parameters e.g., the dosage and the permeability of the blood brain barrier (BBB), impacting the outcome of the clinical effectiveness of the extract are also discussed. Overall, the findings summarized in this review suggest that, a better understanding of the neuroprotective mechanisms of EGb761 may contribute to better understanding of the effectiveness and complexity of this herb and may also be helpful for design of therapeutic strategies in future clinical practice. Therefore, in future clinical studies, different factors that could interfere with the effect of EGb761 should be considered. Full article
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))

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