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Neuroprotective Effects (neuroprotective + effects)
Selected AbstractsNeuroprotective Effects of Currently Used Antidotes in Tabun-Poisoned RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2003í Kassa The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hr and 7 days after tabun challenge. The results indicate that atropine alone is not able to protect the rats from the lethal effects of tabun. Three non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine alone died within 24 hr. On the other hand, atropine combined with all tested oximes allows all tabun-poisoned rats to survive at least 7 days following tabun challenge. Obidoxime combined with atropine seems to be the most effective antidotal treatment for the elimination of tabun-induced neurotoxicity in the case of lethal poisoning among tested antidotal mixtures. The antidotal mixture consisting of atropine and HI-6 is significantly less effective than the combination of atropine with obidoxime in the elimination of tabun-induced neurotoxicity in rats at 24 hr following tabun challenge. Pralidoxime in combination with atropine appears to be practically ineffective to decrease tabun-induced neurotoxicity at 24 hours as well as 7 days following tabun poisoning. Due to its neuroprotective effects, obidoxime seems to be the most effective and most suitable oxime for the antidotal treatment of acute tabun exposure among currently used oximes. Thus, the replacement of obidoxime by a more effective acetylcholinesterase reactivator for soman poisoning, the oxime HI-6, can to a small extent diminish the neuroprotective efficacy of antidotal treatment in the case of acute tabun poisonings. [source] Neuroprotective Effects of N -Alkyl-1,2,4-oxadiazolidine-3,5-diones and Their Corresponding Synthetic Intermediates N -Alkylhydroxylamines and N -1-Alkyl-3-carbonyl-1-hydroxyureas against in,vitro Cerebral IschemiaCHEMMEDCHEM, Issue 1 2010Alain, Cesar Biraboneye Abstract Herein we report the synthesis and neuroprotective effects of new N -alkyl-1,2,4-oxadiazolidine-3,5-diones and their corresponding synthetic intermediates, N -alkylhydroxylamines and N -1-alkyl-3-carbonyl-1-hydroxyureas, in an in,vitro model of ischemia. We found five analogues that protect HT22 cells from death in the concentration range of 1,5,,M. Because members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the newly synthesized analogues. The results indicate that these compounds provide neuroprotection through distinct mechanisms of action. [source] Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action,GLIA, Issue 1 2009You-Joung Kim Abstract Parkinson's disease (PD) is a common, progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Numerous studies have provided evidence suggesting that neuroinflammation plays an important role in the pathogenesis of PD. In this study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether human mesenchymal stem cells (hMSCs) have a protective effect on the dopaminergic system through anti-inflammatory mechanisms. The hMSC treatment significantly decreased LPS-induced microglial activation, tumor necrosis factor (TNF)-,, inducible nitric oxide synthase (iNOS) mRNA expression, and production of NO and TNF-, compared with the LPS-only treatment group. In co-cultures of microglia and mesencephalic dopaminergic neurons, hMSC treatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells. The hMSC treatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the SN was considerably decreased and was clearly accompanied by a decrease in activation of microglia, as well as TNF-, and iNOS mRNA expression and production of TNF-,. These data suggest that hMSCs have a neuroprotective effect on dopaminergic neurons through anti-inflammatory actions mediated by the modulation of microglial activation. Along with various trophic effects and trans-differentiational potency, the anti-inflammatory properties of MSCs could have major therapeutic implications in the treatment of PD. © 2008 Wiley-Liss, Inc. [source] Neuroprotective effects of a combination of dexmedetomidine and hypothermia after incomplete cerebral ischemia in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2010K. SATO Background: Dexmedetomidine and hypothermia are known to reduce neuronal injury following cerebral ischemia. We examined whether a combination of dexmedetomidine and hypothermia reduces brain injury after transient forebrain ischemia in rats to a greater extent than either treatment alone. Methods: Thirty-eight male Sprague,Dawley rats were anesthetized with fentanyl and nitrous oxide in oxygen. Four groups were tested: group C (saline 1 ml/kg, temporal muscle temperature 37.5 °C); group H (saline 1 ml/kg, 35.0 °C); group D (dexmedetomidine 100 ,g/kg, 37.5 °C); and group DH (dexmedetomidine 100 ,g/kg, 35.0 °C). Dexmedetomidine or saline was administered intraperitoneally 30 min before ischemia. Cerebral ischemia was produced by right carotid artery ligation with hemorrhagic hypotension (mean arterial pressure 40 mmHg) for 20 min. Neurologic outcome was evaluated at 24, 48, and 72 h after ischemia. Histopathology was evaluated in the caudate and hippocampus at 72 h after ischemia. Results: Neurologic outcome was significantly better in the group DH than the group C (P<0.05), whereas it was similar between the group DH and the groups D or H. Survival rate of the hippocampal CA1 neurons was significantly greater in groups D, H, and DH than group C (P<0.05). Histopathologic injury in the caudate section was significantly less in groups H and DH than group C (P<0.05). Conclusion: The combination of dexmedetomidine and hypothermia improved short-term neurologic outcome compared with the control group, whereas the combination therapy provided comparable neuroprotection with either of the two therapies alone. [source] Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat modelsAGING CELL, Issue 2 2010Li-Fang Hu Summary Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H2S, a novel biological gas) on PD. The endogenous H2S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H2S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H2S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-, and nitric oxide) in the striatum via NF-,B pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD. [source] Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neuronesJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Julian Bösel Abstract Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygen,glucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen,glucose deprivation or apoptotic cell death. This anti-excitototoxic effect was evident with 2,4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications. [source] Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNFJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Ann D. Cohen Abstract Unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) causes a loss of dopamine (DA) in the ipsilateral striatum and contralateral motor deficits. However, if a cast is placed on the ipsilateral limb during the first 7 days following 6-OHDA infusion, forcing the animal to use its contralateral limb, both the behavioral and neurochemical deficits are reduced. Here, we examine the effect of forced reliance on a forelimb during the 7 days prior to ipsilateral infusion of 6-OHDA on the deficits characteristic of this lesion model. Casted animals displayed no behavioral asymmetries as measured 14,28 days postlesion and a marked attenuation in the loss of striatal DA and its metabolites at 30 days. In addition, animals receiving a unilateral cast alone had an increase in glial cell-line derived neurotrophic factor (GDNF) protein in the striatum corresponding to the overused limb. GDNF increased within 1 day after the onset of casting, peaked at 3 days, and returned to baseline within 7 days. These results suggest that preinjury forced limb-use can prevent the behavioral and neurochemical deficits to the subsequent administration of 6-OHDA and that this may be due in part to neuroprotective effects of GDNF. [source] Neuroprotective effects of bcl-2 overexpression in hippocampal cultures: interactions with pathways of oxidative damageJOURNAL OF NEUROCHEMISTRY, Issue 4 2002Sarah Howard Abstract Overexpression of bcl-2protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons. [source] NAALADase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS)JOURNAL OF NEUROCHEMISTRY, Issue 2002A. G. Thomas Chronic glutamate toxicity is implicated in the pathogenesis of ALS. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. Catabolism of NAAG by N-acetylated-,-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II), yields N-acetyl aspartate (NAA) and glutamate. Since prior studies demonstrate an up-regulation of NAALADase in motor cortex and increased levels of NAA and glutamate in the CSF of ALS patients, we hypothesized that inhibition of NAALADase could protect against neuronal degeneration in ALS. Neuroprotective effects of two NAALADase inhibitors were assessed. 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) decreased motor neuron loss and prevented loss of choline acetyltransferase (ChAT) activity in an in vitro model of ALS wherein chronic glutamate toxicity was induced by blocking glutamate transport. Gross morphology was preserved in 2-PMPA-treated cultures. In a SOD-1 transgenic mouse model of ALS, oral administration of a structurally different NAALADase inhibitor (GPI 5693) increased survival by 29 days and delayed onset of clinical symptoms by 17 days. Preliminary analysis of spinal cord pathology revealed severe neuronal depletion and astrocytosis with white matter changes in control mice. In mice treated with GPI 5693, normal neuronal populations with modest vacuolar changes were observed. These data suggest that NAALADase inhibition may provide an exciting therapeutic approach to the devastating disease, ALS. [source] Neuroprotective effects of an immunosuppressant agent on diffusion/perfusion mismatch in transient focal ischemiaMAGNETIC RESONANCE IN MEDICINE, Issue 6 2004Toshihiko Ebisu Abstract The immunosuppressant FK506 (tacrolimus) exerts potent neuroprotection following focal ischemia in animals; however, the separate effects of FK506 on the ischemic core and penumbra have not been reported. The ischemic penumbra is clinically defined as the difference between a large abnormal area on perfusion-weighted imaging (PWI) and a smaller lesion on diffusion-weighted imaging (DWI). The goal of this study was to determine the effect of FK506 on DWI/PWI match and mismatch areas in transient focal ischemia in rats. Twelve rats were subjected to 1 hr of transient middle cerebral artery (MCA) occlusion, and given an intravenous injection of a placebo (N = 6) or 1 mg/kg FK506 (N = 6) immediately before reperfusion. Magnetic resonance imaging (MRI) was performed during MCA occlusion, and 0.5, 1, and 24 hr after reperfusion. FK506 significantly protected the ischemic brain only in the mismatch cortex where the initial apparent diffusion coefficient (ADC) was normal and there was a mild reduction of cerebral blood flow (CBF). This is the first report to describe the protective effects of FK506 on ischemic penumbra, as measured by DWI/PWI mismatch. The findings provide direct evidence for the utility of DWI/PWI mismatch as a guideline for therapeutic intervention with FK506. Magn Reson Med 51:1173,1180, 2004. © 2004 Wiley-Liss, Inc. [source] 6-Formylpterin protects retinal neurons from transient ischemia,reperfusion injury in rats: A morphological and immunohistochemical studyNEUROPATHOLOGY, Issue 3 2003Taisaku Funakoshi Neuroprotective effects of 6-formylpterin (6FP) on transient retinal ischemia,reperfusion injury were evaluated in rats by means of counting the number of retinal ganglion cells, measuring the thicknesses of the inner plexiform and inner nuclear layers, and by immunohistochemical detection of apoptotic cells in the retina. Sixty-one Sprague,Dawley rats (12 weeks, male, 295,330 g) were subjected to transient retinal ischemia,reperfusion by elevated intra-ocular pressure (80 mmHg for 60 min). Intraperitoneal injection of 6FP (3.8 mg/kg) was performed before or after ischemia. The retina was histologically better preserved in rats with 6FP treatment than without 6FP treatment. 6FP showed more strong neuroprotective effects when it was administered before ischemia. The number of single-stranded DNA-positive cells in the retina also decreased remarkably in rats with 6FP treatment, especially when administered before ischemia. These results suggest that 6FP protects retinal neurons from transient ischemia,reperfusion injury, at least in part by inhibiting apoptotic cell death. [source] Neuroprotective effects of Triticum aestivum L. against ,-Amyloid-induced cell death and memory impairmentsPHYTOTHERAPY RESEARCH, Issue 1 2010Jung-Hee Jang Abstract ,-Amyloid (A,) is a key component of senile plaques, neuropathological hallmarks of Alzheimer's disease (AD) and has been reported to induce cell death via oxidative stress. This study investigated the protective effects of Triticum aestivum L. (TAL) on A,-induced apoptosis in SH-SY5Y cells and cognitive dysfunctions in Sprague-Dawley (SD) rats. Cells treated with A, exhibited decreased viability and apoptotic features, such as DNA fragmentation, alterations in mitochondria and an increased Bax/Bcl-2 ratio, which were attenuated by TAL extract (TALE) pretreatment. To elucidate the neuroprotective mechanisms of TALE, the study examined A,-induced oxidative stress and cellular defense. TALE pretreatment suppressed A,-increased intracellular accumulation of reactive oxygen species (ROS) via up-regulation of glutathione, an essential endogenous antioxidant. To further verify the effect of TALE on memory impairments, A, or scopolamine was injected in SD rats and a water maze task conducted as a spatial memory test. A, or scopolamine treatment increased the time taken to find the platform during training trials, which was decreased by TALE pretreatment. Furthermore, one of the active components of TALE, total dietary fiber also effectively inhibited A,-induced cytotoxicity and scopolamine-caused memory deficits. These results suggest that TALE may have preventive and/or therapeutic potential in the management of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source] Neuroprotective effects of Brazilian green propolis and its main constituents against oxygen-glucose deprivation Stress, with a gene-expression analysisPHYTOTHERAPY RESEARCH, Issue 10 2009Yoshimi Nakajima Abstract Our purpose was to investigate the neuroprotective effects (and the underlying mechanism) exerted by water extract of Brazilian green propolis (WEP) and its main constituents against the neuronal damage induced by oxygen-glucose deprivation (OGD)/reoxygenation in retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). Cell damage was induced by OGD 4 h plus reoxygenation 18 h exposure. In RGC-5, and also in PC12 (rat pheochromocytoma, neuronal cells), WEP and some of its main constituents attenuated the cell damage. At the end of the period of OGD/reoxygenation, RNA was extracted and DNA microarray analysis was performed to examine the gene-expression profile in RGC-5. Expression of casein kinase 2 (CK2) was down-regulated and that of Bcl-2-related ovarian killer protein (Bok) was up-regulated following OGD stress, results that were confirmed by quantitative reverse transcriptase-PCR (qRT-PCR). These effects were normalized by WEP. Our findings indicate that WEP has neuroprotective effects against OGD/reoxygenation-induced cell damage and that certain constituents of WEP (caffeoylquinic acid derivatives, artepillin C, and p -coumaric acid) may be partly responsible for its neuroprotective effects. Furthermore, the protective mechanism may involve normalization of the expressions of antioxidant- and apoptosis-related genes (such as CK2 and Bok, respectively). Copyright © 2009 John Wiley & Sons, Ltd. [source] Retracted: Antiaging effect of purslane herb aqueous extracts and its mechanism of ActionPHYTOTHERAPY RESEARCH, Issue 9 2009Huang Hao The following article from Phytotherapy Research, Antiaging effect of purslane herb aqueous extracts and its mechanism of Action by Huang Hao, Yu Nancai, Fu Lei, Su Wen, Huang Guofu, Wu Yanxia, Huang Hanju, Liu Qian published online on 15th April 2009 in Wiley InterScience (www.interscience.wiley.com) has been retracted by agreement between the journal Editor in Chief, Elizabeth Williamson and John Wiley & Sons, Ltd. The retraction has been agreed due to overlap with the following article: Zhang Hongxing, Yu Nancai, Huang Guofu, Shao Jianbo, Wu Yanxia, Huang Hanju, Liu Qian, Ma Wei, Yi Yandong and Huang Hao. Neuroprotective effects of purslane herb aquenous extracts against d-galactose induced neurotoxicity. Chemico-Biological Interactions 170: 3, pp.145-152. Copyright © 2009 John Wiley & Sons, Ltd. [source] Neuroprotective effects of Tanshinone IIA on permanent focal cerebral ischemia in mice,PHYTOTHERAPY RESEARCH, Issue 5 2009Kenan Dong Abstract The objective of this study was to evaluate whether Tanshinone IIA (TSA) was neuroprotective in permanent focal cerebral ischemia and to determine the possible mechanisms of its neuroprotection. Mice were subjected to permanent middle cerebral artery occlusion. The neuroprotection of TSA was investigated with respect to neurological deficit scores and infarct volume. Biochemical analyses for malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in serum, and nitric oxide (NO) content and the inducible nitric oxide synthase (iNOS) activity in brain tissue were performed at 24 h after ischemia. Immunohistochemistry was used to measure the expression of iNOS. In vitro, the effects of TSA were tested in the cultured astrocytes exposed to hydrogen dioxide (H2O2). TSA (5, 10 and 20 mg/kg, i.p.) significantly reduced the infarct volume and improve neurological deficit. TSA also significantly increased the activity of SOD after 24 h of ischemia and decreased the MDA level, NO content, and iNOS expression. In vitro, the translocation of NF- ,B was inhibited by TSA and the survival rate of astrocytes was markedly increased and the NO production was decreased. In conclusion, these results illustrated that TSA protected the brain from ischemic injury by suppressing the oxidative stress and the radical-mediated inflammatory insult. Copyright © 2008 John Wiley & Sons, Ltd. [source] Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cellsPHYTOTHERAPY RESEARCH, Issue 3 2005Sung-Soo Kim Abstract Oxidative stress plays an important role in the pathological processes of a variety of neurodegenerative diseases. The neuroprotective effects of 3,5-diCQA and 3,4-diCQA, two caffeoylquinic acid derivatives present in Dipsacus asper, on hydrogen peroxide (H2O2)-induced neuronal cell damage were evaluated in this study. SH-SY5Y cells treated with H2O2 exhibited a decrease in survival and intracellular glutathione and also an increase in the caspase-3 activity. However, pretreatment of cells with 3,5-diCQA attenuated the neuronal death and caspase-3 activation induced by H2O2. In addition, 3,5-diCQA restored H2O2 -induced depletion of intracellular glutathione. 3,5-diCQA showed significant protective effects although it could not completely suppress H2O2 -induced cell injury to control levels. The data suggest that 3,5-diCQA might be a potential therapeutic agent for treating or preventing neurodegenerative diseases implicated with oxidative stress. Copyright © 2005 John Wiley & Sons, Ltd. [source] Neuroprotective effects of estrogen therapy for cognitive and neurobiological profiles of monkey models of menopauseAMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009Mary Lou Voytko Abstract Many postmenopausal women question whether to start or continue hormone therapy because of recent clinical trial negative results. However, evidence from other studies of postmenopausal women, and from studies in menopausal monkeys, indicate that estrogen has neurocognitive protective effects, particularly when therapy is initiated close to the time of menopause before neural systems become increasingly compromised with age. In this review, we present studies of menopausal women and female monkeys that support the concept that estrogen therapies protect both cognitive function and neurobiological processes. Am. J. Primatol. 71:794,801, 2009. © 2009 Wiley-Liss, Inc. [source] Neuroprotective effects of zonisamide target astrocyteANNALS OF NEUROLOGY, Issue 2 2010Masato Asanuma MD Objective Recent double-blind, controlled trials in Japan showed that the antiepileptic agent zonisamide (ZNS) improves the cardinal symptoms of Parkinson's disease. Glutathione (GSH) exerts antioxidative activity through quenching reactive oxygen species and dopamine quinone. GSH depletion within dopaminergic neurons impairs mitochondrial complex I activity, followed by age-dependent nigrostriatal neurodegeneration. This study examined changes in GSH and GSH synthesis-related molecules, and the neuroprotective effects of ZNS on dopaminergic neurodegeneration using 6-hydroxydopamine,injected hemiparkinsonian mice brain and cultured neurons or astrocytes. Methods and Results ZNS increased both the cell number and GSH levels in astroglial C6 cells, but not in dopaminergic neuronal CATH.a cells. Repeated injections of ZNS (30mg/kg intraperitoneally) for 14 days also significantly increased GSH levels and S100,-positive astrocytes in mouse basal ganglia. Repeated ZNS injections (30mg/kg) for 7 days in the hemiparkinsonian mice increased the expression of cystine/glutamate exchange transporter xCT in activated astrocytes, which supply cysteine to neurons for GSH synthesis. Treatment of these mice with ZNS also increased GSH levels and completely suppressed striatal levodopa,induced quinone formation. Reduction of nigrostriatal dopamine neurons in the lesioned side of hemiparkinsonian mice was significantly abrogated by repeated injections of ZNS with or without adjunctive levodopa starting 3 weeks after 6-hydroxydopamine lesioning. Interpretation These results provide new pharmacological evidence for the effects of ZNS. ZNS markedly increased GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation via S100, production or secretion. ZNS acts as a neuroprotectant against oxidative stress and progressive dopaminergic neurodegeneration. ANN NEUROL 2010;67:239,249 [source] Neuroprotective effects of pramipexole against tunicamycin-induced cell death in PC12 cellsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2009Hitoshi Nakayama Summary 1Pramipexole (PPX), a dopamine D2 and D3 receptor agonist, exerts neuroprotective effects via both dopamine receptor-mediated and non-dopaminergic mechanisms. In the present study, we demonstrate that PPX reduces the toxicity of tunicamycin, a typical endoplasmic reticulum (ER) stressor, in PC12h cells, a subline of PC12 cells. 2The PC12h cells were treated with 300 ,mol,/,L PPX in the presence of 0.5 ,mol,/,L tunicamycin for 24 h. The neuroprotective effects of PPX against tunicamycin-induced cell death were evaluated using 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, Hoechst 33258 staining and western blot analysis. 3Tunicamycin (0.2, 0.3 and 0.5 ,g,/,mL) dose-dependently decreased MTT activity and increased LDH release from PC12h cells. Treatment with 300 ,mol,/,L PPX rescued the tunicamycin-induced decrease in cell viability. 4Spiperone (10 ,mol,/,L), a dopamine D2 and D4 receptor antagonist, had no effect on PPX neuroprotection against tunicamycin in these cells. Marker proteins of ER stress and apoptosis are known to be upregulated by tunicamycin, but we detected no significant effects of PPX on these factors. 5In conclusion, we speculate that a combination of several mechanisms may be involved in PPX-induced neuroprotection. [source] Environmental complexity and central nervous system development and functionDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2004Mark H. Lewis Abstract Environmental restriction or deprivation early in development can induce social, cognitive, affective, and motor abnormalities similar to those associated with autism. Conversely, rearing animals in larger, more complex environments results in enhanced brain structure and function, including increased brain weight, dendritic branching, neurogenesis, gene expression, and improved learning and memory. Moreover, in animal models of CNS insult (e.g., gene deletion), a more complex environment has attenuated or prevented the sequelae of the insult. Of relevance is the prevention of seizures and attenuation of their neuropathological sequelae as a consequence of exposure to a more complex environment. Relatively little attention, however, has been given to the issue of sensitive periods associated with such effects, the relative importance of social versus inanimate stimulation, or the unique contribution of exercise. Our studies have examined the effects of environmental complexity on the development of the restricted, repetitive behavior commonly observed in individuals with autism. In this model, a more complex environment substantially attenuates the development of the spontaneous and persistent stereotypies observed in deer mice reared in standard laboratory cages. Our findings support a sensitive period for such effects and suggest that early enrichment may have persistent neuroprotective effects after the animal is returned to a standard cage environment. Attenuation or prevention of repetitive behavior by environmental complexity was associated with increased neuronal metabolic activity, increased dendritic spine density, and elevated neurotrophin (BDNF) levels in brain regions that are part of cortical,basal ganglia circuitry. These effects were not observed in limbic areas such as the hippocampus. MRDD Research Reviews 2004;10:91,95. © 2004 Wiley-Liss, Inc. [source] Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus.DEVELOPMENTAL NEUROBIOLOGY, Issue 9 2006The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective Abstract The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5,-dihydroprogesterone (DHP) by the enzyme 5,-reductase. DHP is subsequently reduced to 3,,5,-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3,-hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (MPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5,-reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3,-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Letter: Antiepileptogenic and neuroprotective effects of erythropoietin: Recent dataEPILEPSIA, Issue 6 2009Mohamad A. Mikati No abstract is available for this article. [source] Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regeliiEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009D. H. Kim Abstract Background, Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exhibits various biological properties, including chemopreventive, antioxidant and neuroprotective effects. In this study, we showed that celastrol inhibits inflammatory reactions in macrophages and protects mice from skin inflammation. Materials and methods, Anti-inflammatory effects of celastrol (0,1 ,M) were examined in lipopolysaccharide (LPS)-stimulated RAW 264·7 macrophages. To investigate the effects of celastrol (0,50 ,g per mice) in vivo, activation of myeloperoxidase (MPO) and histological assessment were examined in the 12- O -tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear oedema model. Results, Our in vitro experiments showed that celastrol suppressed not only LPS-stimulated generation of nitric oxide and prostaglandin E2, but also expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW264·7 cells. Similarly, celastrol inhibited LPS-induced production of inflammatory cytokines, including tumour necrosis factor-, and interleukin-6. In an animal model, celastrol protected mice from TPA-induced ear oedema, possibly by inhibiting MPO activity and production of inflammatory cytokines. Conclusions, Our data suggest that celastrol inhibits the production of inflammatory mediators and is a potential target for the treatment of various inflammatory diseases. [source] Tocotrienols and cancer: Beyond antioxidant activityEUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY, Issue 4 2007Kalanithi Nesaretnam Abstract The edible oil industry has emerged as an important provider of raw material for the extraction of vitamin,E. Vegetable oils, especially the seed oils, are rich sources of tocopherols. However, in palm oil, vitamin,E occurs as a complex mixture of tocopherols and tocotrienols. Various tocotrienol isomers of vitamin,E in palm oil have been reported to possess interesting biological and physiological properties not generally evident with tocopherol-rich vitamin,E preparations. They include potential blood cholesterol-lowering and cardioprotective effects, more efficient antioxidant activity in biological systems, and possible anti-cancer and neuroprotective effects. With the emergence of palm oil as the largest edible oil in world markets, technology is now available to extract tocotrienol-rich palm vitamin,E. Initiatives in Malaysia to manufacture biodiesel will further generate large amounts of micronutrients, especially tocotrienols, to be available to the nutraceutical and functional food industry. [source] Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind studyEUROPEAN JOURNAL OF NEUROLOGY, Issue 9 2006M. Mazza The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective effects in neurodegenerative diseases of multifactorial origin. There is still debate about the efficacy of Ginkgo biloba special extract EGb 761 compared with second-generation cholinesterase inhibitors in the treatment of mild to moderate Alzheimer's dementia. Our aim is to assess the efficacy of the Ginkgo biloba special extract E.S. in patients with dementia of the Alzheimer type in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with donepezil and placebo. The trial was designed as a 24-week randomized, placebo-controlled, double-blind study. Patients aged 50,80 years, suffering from mild to moderate dementia, were allocated into one of the three treatments: Ginkgo biloba (160 mg daily dose), donepezil (5 mg daily dose), or placebo group. The degree of severity of dementia was assessed by the Syndrom Kurz test and the Mini-Mental State Examination. Clinical Global Impression score was recorded to assess the change in the patients' conditions and the therapeutic efficacy of tested medications. Our results confirm the clinical efficacy of Ginkgo biloba E.S. (Flavogin) in the dementia of the Alzheimer type, comparable with donepezil clinical efficacy. There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia. This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type and could be a valid contribution in this debate. Our study suggests that there is no evidence of relevant differences in the efficacy of EGb 761 and donepezil in the treatment of mild to moderate Alzheimer's dementia, so the use of both substances can be justified. In addition, this study contributes to establish the efficacy and tolerability of the Ginkgo biloba special extract E.S. in the dementia of the Alzheimer type with special respect to moderately severe stages. [source] Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2008Meng-Yang Zhu Abstract Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with ,-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress. [source] Recombinant human erythropoietin suppresses symptom onset and progression of G93A-SOD1 mouse model of ALS by preventing motor neuron death and inflammationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Seong-Ho Koh Abstract Multifactorial pathogenic mechanisms, including inflammation, attenuated survival signals and enhanced death signals, are involved in amyotrophic lateral sclerosis (ALS). Erythropoietin (EPO) has recently been highlighted as a cytokine with various potent neuroprotective effects, including reduction of inflammation, enhancement of survival signals and prevention of neuronal cell death. This study was undertaken to evaluate the effect of recombinant human EPO (rhEPO) on ALS model mice. We treated 96 ALS model mice with vehicle only, or 1, 2.5 or 5 iµ of rhEPO/g of mouse once every other week after they were 60 days old. The treatment significantly prolonged symptom onset and life span, preserved more motor neurons, enhanced survival signals, and attenuated inflammatory signals in a dose-dependent manner. These data suggest that treatment with rhEPO represents a potential therapeutic strategy for ALS. [source] Astrocytic factors protect neuronal integrity and reduce microglial activation in an in vitro model of N -methyl- d -aspartate-induced excitotoxic injury in organotypic hippocampal slice culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2001Nils P. Hailer Abstract Acute CNS lesions lead to neuronal injury and a parallel glial activation that is accompanied by the release of neurotoxic substances. The extent of the original neuronal damage can therefore be potentiated in a process called secondary damage. As astrocytes are known to secrete immunomodulatory and neuroprotective substances, we investigated whether astrocytic factors can attenuate the amount of neuronal injury as well as the degree of microglial activation in a model of excitotoxic neurodegeneration. Treatment of organotypic hippocampal slice cultures with N-methyl- d -aspartate (NMDA) resulted in a reproducible loss of viable granule cells, partial destruction of the regular hippocampal cytoarchitecture and a concomitant accumulation of amoeboid microglial cells at sites of neuronal damage. Astrocyte-conditioned media reduced the amount of NMDA-induced neuronal injury by 45.3%, diminished the degree of microglial activation and resulted in an improved preservation of the hippocampal cytoarchitecture. Transforming growth factor (TGF)-, failed to act as a neuroprotectant and even enhanced the amount of neuronal injury by 52.5%. Direct effects of astrocytic factors on isolated microglial cells consisted of increased microglial ramification and down-regulated expression of intercellular adhesion molecule-1, whereas incubation with TGF-, had no such effects. In summary, our findings show that hitherto unidentified astrocyte-derived factors that are probably not identical with TGF-, can substantially enhance neuronal survival, either by eliciting direct neuroprotective effects or by modulating the microglial response to neuronal injury. [source] P2Y1 receptor signaling enhances neuroprotection by astrocytes against oxidative stress via IL-6 release in hippocampal culturesGLIA, Issue 3 2009Takumi Fujita Abstract Cell survival is a critical issue in the onset and progression of neurodegenerative diseases and following pathological events including ischemia and traumatic brain injury. Oxidative stress is the main cause of cell damage in such pathological conditions. Here, we report that adenosine 5,-triphosphate (ATP) protects hippocampal astrocytes from hydrogen peroxide (H2O2)-evoked oxidative injury in astrocyte monocultures. The effect of ATP was prevented by a selective antagonist of or siRNAs against P2Y1R. Interestingly, in astrocyte-neuron cocultures, ATP also produced neuroprotective effects against H2O2 -evoked neuronal cell death, whereas ATP did not produce any neuroprotective effects in monocultures. The ATP-induced neuroprotection in cocultures was completely inhibited by silencing of astrocytic P2Y1R expression, indicating that ATP acts on astrocytes and enhances their neuroprotective functions by activating P2Y1R. Furthermore, this neuroprotective effect was mimicked by applying conditioned medium from astrocytes that had been stimulated by ATP, implying an involvement of diffusible factors from astrocytes. We found that, in both purified astrocyte cultures and astrocyte-neuronal cocultures, ATP and the P2Y1R agonist 2-methylthioadenosine 5, diphosphate (2MeSADP) induced the release of interleukin-6 (IL-6), but this did not occur in neuron monocultures. Moreover, exogenous IL-6 produced a neuroprotective effect, and the neuroprotection induced by P2Y1R-stimulated astrocytes was prevented in the presence of an anti-IL-6 antibody. Taken together, these results suggest that P2Y1R-stimulated astrocytes protect against neuronal damage induced by oxidative stress, and that IL-6 is a crucial signaling molecule released from astrocytes. Thus, activation of P2Y1R in astrocytes may rescue neurons from secondary cell death under pathological conditions. © 2008 Wiley-Liss, Inc. [source] Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injuryGLIA, Issue 3 2008Aaron Y. Lai Abstract Microglial activation has been reported to promote neurotoxicity and also neuroprotective effects. A possible contributor to this dichotomy of responses may be the degree to which proximal neurons are injured. The aim of this study was to determine whether varying the severity of neuronal injury influenced whether microglia were neuroprotective or neurotoxic. We exposed cortical neuronal cultures to varying degrees of hypoxia thereby generating mild (<20% death, 30min hypoxia), moderate (40,60% death, 2 h hypoxia), or severe (>70% death, 6 h hypoxia) injuries. Twenty-four hours after hypoxia, the media from the neuronal cultures was collected and incubated with primary microglial cultures for 24 h. Results showed that the classic microglial proinflammatory mediators including inducible nitric oxide synthase, tumor necrosis factor ,, and interleukin-1-, were upregulated only in response to mild neuronal injuries, while the trophic microglial effectors brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were upregulated in response to all degrees of neuronal injury. Microglia stimulated with media from damaged neurons were co-cultured with hypoxic neurons. Microglia stimulated by moderate, but not mild or severe damage were neuroprotective in these co-cultures. We also showed that the severity-dependent phenomenon was not related to autocrine microglial signaling and was dependent on the neurotransmitters released by neurons after injury, namely glutamate and adenosine 5,-triphosphate. Together our results show that severity of neuronal injury is an important factor in determining microglial release of "toxic" versus "protective" effectors and the resulting neurotoxicity versus neuroprotection. © 2007 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||