Objective To investigate the mechanisms of excitotoxic effects of glutamate on human neuroblastoma SH-SY5Y cells. Methods SH-SY5Y cell viability was measured by MTT assay. Other damaged profile was detected by lactate...Objective To investigate the mechanisms of excitotoxic effects of glutamate on human neuroblastoma SH-SY5Y cells. Methods SH-SY5Y cell viability was measured by MTT assay. Other damaged profile was detected by lactate dehydrogenase （LDH） release and by 4＇, 6-diamidino-2-phenylindole （DAPI） staining. The cytosolic calcium concentration was tested by calcium influx assay. The glutamate-induced oxidative stress was analyzed by cytosolic glutathione assay, superoxide dismutase （SOD） assay and extracellular malondialdehyde （MDA） assay. Results Glutamate treatment caused damage in SH- SY5Y cells, including the decrease of cell viability, the increase of LDH release and the alterations of morphological structures. Furthermore, the concentration of cytoplasmic calcium in SH-SY5Y cells was not changed within 20 min following glutamate treatment, while cytosolic calcium concentration significantly increased within 24 h after glutamate treatment, which could not be inhibited by MK801, an antagonist of NMDA receptors, or by LY341495, an antagonist of metabotropic glutamate receptors. On the other hand, oxidative damage was observed in SH-SY5Y cells treated with glutamate, including decreases in glutathione content and SOD activity, and elevation of MDA level, all of which could be alleviated by an antioxidant Tanshinone IIA （Tan IIA, a major active ingredient from a Chinese plant Salvia Miltiorrhiza Bge）. Conclusion Glutamate exerts toxicity in human neuroblastoma SH-SY5Y cells possibly through oxidative damage, not through calcium homeostasis destruction mediated by NMDA receptors.展开更多
Objective To investigate a possibility of repairing damaged brain by intracerebroventricular transplantation of neural stem cells （NSCs） in the adult mice subjected to glutamate-induced excitotoxic injury. Methods M...Objective To investigate a possibility of repairing damaged brain by intracerebroventricular transplantation of neural stem cells （NSCs） in the adult mice subjected to glutamate-induced excitotoxic injury. Methods Mouse NSCs were isolated from the brains of embryos at 15-day postcoitum （dpc）. The expression of nestin, a special antigen for NSC, was detected by immunocytochemistry. Immunofluorescence staining was carried out to observe the survival and location of transplanted NSCs. The animals in the MSG＋NSCs group received intracerebroventricular transplantation of NSCs （approximately 1.0×10^5 cells） separately on day 1 and day 10 after 10-d MSG exposure （4.0 g/kg per day）. The mice in control and MSG groups received intracerebroventricular injection of Dulbecco＇s minimum essential medium （DMEM） instead of NSCs. On day 11 after the last NSC transplantation, the test of Y-maze discrimination learning was performed, and then the histopathology of the animal brains was studied to analyze the MSG-induced functional and morphological changes of brain and the effects of intracerebroventricular transplantation of NSCs on the brain repair. Results The isolated cells were Nestin-positive. The grafted NSCs in the host brain were region-specifically survived at 10-d post-transplantation. Intracerebroventricular transplantation of NSCs obviously facilitated the brain recovery from glutamate-induced behavioral disturbances and histopathological impairs in adult mice. Conclusion Intracerebroventricular transplantation of NSCs may be feasible in repairing diseased or damaged brain tissue.展开更多
AIM: To investigate whether bis (7)-tacrine, a multifunctional drug, inhibits N-methyl-D-aspartate (NMDA) -activated current in retinal ganglion cells (RGC) and provides neuroprotection against retinal cell damage. ME...AIM: To investigate whether bis (7)-tacrine, a multifunctional drug, inhibits N-methyl-D-aspartate (NMDA) -activated current in retinal ganglion cells (RGC) and provides neuroprotection against retinal cell damage. METHODS: Purified RGC cultures were obtained from retinas of 1-3 days old Sprague-Dawley (SD) rats, following a two-step immunopanning procedure. After 7 days of cultivation, the inhibition of NMDA-activated current by bis(7) -tacrine was measured by using patch-clamp recording techniques. In animal experiments, RGCs were damaged after intravitreal injection of NMDA (5 mu L, 40nmol) in adult rats. Bis (7)-tacrine(0.05, 0.1, 0.2mg/kg) or memantine(20mg/kg) was intraperitoneal administered to the rats fifteen minutes before intravitreally injection of NMDA. RGC damage was analyzed by histologic techniques, TUNEL and retrograde labeling techniques. RESULTS: Whole-cell patch-clamp recordings demonstrated that NMDA (30 mu mol/L) resulted in approximately -50 pA inward currents that were blocked by bis (7)-tacrine (1 mu mol/L). Histological examination and retrograde labeling analysis revealed that bis (7)-tacrine induced a significant neuroprotective effect against NMDA-induced cell damage 7 days after NMDA injection. TUNEL staining showed that pretreatment with bis(7)-tacrine was effective in ameliorating NMDA-induced apoptotic cell loss in the retinal ganglion cell layer 18 hours after injection. CONCLUSION: Bis (7)-tacrine possesses remarkable neuroprotective activities against retinal excitotoxicity through inhibition of NMDA receptors.展开更多
Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to ...Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.展开更多
Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotran...Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,展开更多
Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles...Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles(EVs)secreted by ADSCs(ADSC-EVs)not only have the function of ADSCs,but also have unique advantages including non-immunogenicity,low probability of abnormal growth,and easy access to target cells.In the present study,we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography.In addition,R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium,downregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor(AMPAR)subunit GluA2,and phosphorylation of GluA2 and protein kinase C alpha in vitro.A protein kinase C alpha agonist,12-O-tetradecanoylphorbol 13-acetate,inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells.These findings suggest that ADSCEVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.展开更多
AIM： To explore the more suitable concentration of glutamate or N-methyl-D-aspartic acid（NMDA） for intravitreal injection to establish a rat model of retinal neurodegeneration. METHODS： We injected different doses...AIM： To explore the more suitable concentration of glutamate or N-methyl-D-aspartic acid（NMDA） for intravitreal injection to establish a rat model of retinal neurodegeneration. METHODS： We injected different doses of glutamate（20 or 50 nmol） or NMDA（40 nmol） into the vitreous chambers of rats, then measured the concentration of glutamate and retinal thickness, quantified apoptotic cells and determined the degree of tau hyperphosphorylation at different time points. T-test was used for comparison of two groups. One-way ANOVA and Turkey＇s multiple comparisons test were used for comparisons of different groups, and P values below 0.05 were considered statistically significant.RESULTS： The glutamate level in the rats treated with 50 nmol of glutamate was twice that of the control group and persisted two weeks. Seven days after intravitreal injection of 50 nmol of glutamate, three parameters [inner retinal thickness（IRT）, retinal thickness（RT） and ganglion cell layer（GCL） cell number] were reduced significantly. Furthermore, numerous TUNEL-positive cells were observed in the GCL one day after intravitreal injection of 50 nmol of glutamate, the expression of the apoptosisrelated factor cleaved casepase-3 was markedly increased compared with the expression levels in the other treatment groups, and the expression levels of tau s396 and tau s404 were significantly increased compared with those in the control group.CONCLUSION： This study demonstrates that the intravitreal injection of 50 nmol of glutamate can establish the more effective retinal neurodegeneration animal model relative to other treatment groups.展开更多
Previous studies have shown that mitogen-activated protein kinase （MAPK） signaling pathways are involved in N-methyI-D-aspartate （NMDA）-mediated excitotoxicity. However, a systematic observation or analysis of the...Previous studies have shown that mitogen-activated protein kinase （MAPK） signaling pathways are involved in N-methyI-D-aspartate （NMDA）-mediated excitotoxicity. However, a systematic observation or analysis of the role of these various MAPK pathways in excitotoxicity processes does not exist. The present study further evaluated the role and contribution of three MAPK pathways extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK in an NMDA-mediated excitotoxicity model using MAPK^specific inhibitor. Results demonstrated that c-Jun N-terminal kinase inhibitor SP600125 and/or p38 MAPK inhibitor SB203580 inhibited NMDA-induced reduction in cell viability, as well as reduced NMDA-induced lactate dehydrogenase leakage and reactive oxygen species production. However, PD98059, an inhibitor of extracellular signal-regulated kinase, did not influence this model. Results demonstrated an involvement of c-Jun N-terminal kinase and p38 MAPK, but not extracellular signal-regulated kinase, in NMDA-mediated excitotoxicity in cortical neurons.展开更多
Glutamate（Glu） is the major afferent excitatory neurotransmitter in the auditory system, and excessive Glu may play an important role in cochlear dysfunction. It is unclear how excessive Glu plays roles in cochlear ...Glutamate（Glu） is the major afferent excitatory neurotransmitter in the auditory system, and excessive Glu may play an important role in cochlear dysfunction. It is unclear how excessive Glu plays roles in cochlear dysfunction in cochlear organotypic cultures. In this study neonatal rat cochlear organotypic cultures were prepared, and then the cochlear tissues were incubated with a new medium containing specific concentrations of Glu（0.1, 0.5, 1, 10 or 20 mmol/L） for 24 h, or incubated with the medium containing a concentration of 20 mmol/L Glu for 6, 12, 24 or 72 h, respectively. It was found that when the cochlear tissues were cultured for 24 h, the inner hair cells（IHCs） were damaged at the concentration of 0.5 mmol/L Glu, and with the increases of the concentrations, the injury was gradually aggravated, and 20 mmol/L Glu resulted in the significant loss of IHCs. In the 20 mmol/L Glu groups, the stereocilia bundles were missing or disarrayed on a few IHCs after culture for 6 h and the damage effect was time-dependent. The missing of IHCs was more significant in the basal turn of the cochlea than in the middle turn of the cochlea under the same concentration of Glu exposure. These results suggest that excessive exogenous Glu affects the morphology of IHCs, but not affects the outer hair cells（OHCs） in cochlear organotypic cultures, and the excitotoxic effects are different on IHCs of different parts of the cochlea under the same concentration of Glu exposure.展开更多
Recent studies have demonstrated that ferulic acid[3-（4-hydroxy-3-methoxyphenyl）-2-propenoic acid]and sodium ferulate produce protective effects against glutamate-induced neurotoxicity in adult mice.Danshensu（β-3,...Recent studies have demonstrated that ferulic acid[3-（4-hydroxy-3-methoxyphenyl）-2-propenoic acid]and sodium ferulate produce protective effects against glutamate-induced neurotoxicity in adult mice.Danshensu（β-3,4-dihydroxyphenyl-lactic acid）has a similar molecular structure and pharmacological action to caffeic acid.This study aimed to validate the protection conferred by Danshensu against excitotoxic effects of maternal intragastric administration of monosodium glutamate at late stages of pregnancy in the developing mouse fetal brain.Behavioral tests,as well as histopathological and immunohistochemical examination of hippocampi were performed in filial mice.Results revealed that maternal intragastric administration of excessive monosodium glutamate（1.0,2.0,4.0 g/kg body weight）at a late stage of pregnancy resulted in a series of behavioral disorders（hyperactivity,lesions of learning and memory,and disturbance in cooperation of movement ability under high-altitude stress）,histopathological impairment（neuronal edema,degeneration,necrosis,and hyperplasia）and molecular cellular biological changes（upregulated expression of N-methyI-D-aspartate receptor type 1 and neuropeptide Y in the hippocampal region of the brain of the filial mice from mothers treated with monosodium glutamate）.Simultaneous administration of sodium Danshensu partially reversed the effects of monosodium glutamate on the above mentioned phenomena.These findings indicate that sodium Danshensu exhibits obvious protective effects on the excitotoxicity of monosodium glutamate.展开更多
The retina is a multilayered tissue that develops following a central-to-peripheral gradient. Its structure derives from multipotent precursors, as shown through clonal analysis of retinal cell lineage. These progenit...The retina is a multilayered tissue that develops following a central-to-peripheral gradient. Its structure derives from multipotent precursors, as shown through clonal analysis of retinal cell lineage. These progenitors generate diverse cell types, controlled by complex influences of intrinsic and extrinsic factors （Hatakevama and Kagevama, 2004）.展开更多
During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membra...During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.展开更多
Objective: Our previous studies have revealed that ferulic acid (FA) and sodium ferulate (SF) show significant protective effect on excitotoxicity, the present study was conducted to compare its potential favorable ef...Objective: Our previous studies have revealed that ferulic acid (FA) and sodium ferulate (SF) show significant protective effect on excitotoxicity, the present study was conducted to compare its potential favorable effects of maternal,newborn,and both maternal and newborn intraperitoneal (ip) injection of SF on repair following excitotoxic neuronal damages induced by monosodium glutamate (MSG). Methods: The maternal mice were assigned randomly into seven groups (n = 10 animals in each group): control, 3SF, 20SF, 23SF, MSG, MSG + 3SF, MSG + 20SF, MSG + 23SF groups. The mice at 17 days of pregnancy were treated with or without MSG (2.0 g/kg body weight, ig, once) or/and SF (40 mg/kg body weight, ip), and their offerings treated with or without SF. And then their filial behaviors and hippocampal histopathology were studied. Results: The results showed that maternal, newborn, and both maternal and newborn administration of SF facilitated their filial brain repair, and attenuated the behavioral disorders and histopathological damages of their filial mice in MSG + 3SF, MSG + 20SF, and MSG + 23SF groups in varying degrees. However, the best effects were detected in the filial mice in MSG + 23SF group. Conclusion: Both maternal and newborn administration of SF is conducive to the filial neuronal repair following excitotoxic damages induced by glutamate.展开更多
The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular rec...The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular recanalization treatments such as thrombolysis and mechanical thrombectomy have achieved some success,reperfusion injury remains a significant contributor to the exacerbation of brain injury.This emphasizes the need for developing neuroprotective strategies to mitigate this type of injury.The purpose of this review was to examine the application of nanotechnology in the treatment of ischemic stroke,covering research progress in nanoparticlebased drug delivery,targeted therapy,and antioxidant and anti-inflammatory applications.Nanobased drug delivery systems offer several advantages compared to traditional therapies,including enhanced blood–brain barrier penetration,prolonged drug circulation time,improved drug stability,and targeted delivery.For example,inorganic nanoparticles,such as those based on CeO_(2),have been widely studied for their strong antioxidant capabilities.Biomimetic nanoparticles,such as those coated with cell membranes,have garnered significant attention owing to their excellent biocompatibility and targeting abilities.Nanoparticles can be used to deliver a wide range of neuroprotective agents,such as antioxidants(e.g.,edaravone),anti-inflammatory drugs(e.g.,curcumin),and neurotrophic factors.Nanotechnology significantly enhances the efficacy of these drugs while minimizing adverse reactions.Although nanotechnology has demonstrated great potential in animal studies,its clinical application still faces several challenges,including the long-term safety of nanoparticles,the feasibility of large-scale production,quality control,and the ability to predict therapeutic effects in humans.In summary,nanotechnology holds significant promise for the treatment of ischemic stroke.Future research should focus on further exploring the mechanisms of action of nanoparticles,developing multifunctional nanoparticles,and validating their safety and efficacy through rigorous clinical trials.Moreover,interdisciplinary collaboration is essential for advancing the use of nanotechnology in stroke treatment.展开更多
Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut...Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.展开更多
Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorder...Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorders.Polyphenols,such as quercetin and resveratrol,are plant-derived compounds that activate sirtuins(SIRTs)and have shown promising results in some models of neuronal death,although their effects have been scarcely tested in models of motor neuron degeneration.Methods:In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)into the rat spinal cord tissue.Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days.Then,animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures.Results:We found that the chronic infusion of AMPA[1 mM]caused a progressive motor neuron degeneration,accompanied by astrogliosis and microgliosis,and motor deficits and paralysis of the rear limbs.Quercetin infusion ameliorated AMPA-induced paralysis,rescued motor neurons,and prevented both astrogliosis and microgliosis,and these protective effects were prevented by EX527,a very selective SIRT1 inhibitor.In contrast,neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration,albeit both reduced gliosis.Conclusions:These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism,and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.展开更多
Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various...Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders.The dysregulation of glutamate signaling,leading to excitotoxicity and neuronal cell death,has been a focal point in understanding the underlying mechanisms of these conditions.This has prompted a paradigm shift in neuroprotection research,with a growing emphasis on targeting ionotropic glutamate receptors(iGluRs)to restore glutamatergic homeostasis.This review provides a comprehensive overview of recent advancements in the field of iGluR-targeted neuroprotection.We further investigate the implications of glutamate dysregulation in the central nervous system(CNS)disorders,highlighting the complex interplay between excitotoxicity and neuroprotection.We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage,emphasizing the need for innovative therapeutic approaches.This review provides an extensive survey of the burgeoning field of iGluR-targeted neuroprotection.It showcases the significant potential of a wide array of compounds,encompassing both natural and synthetic agents,to modulate iGluRs and ameliorate excitotoxicity and oxidative stress-induced neuronal damage.These compounds have demonstrated impressive neuroprotective effects in diverse experimental models,from glutamate-induced toxicity to traumatic brain injuries.We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation,heralding a promising era in neuroprotection and CNs disorder management.展开更多
BACKGROUND： Huntington＇s Disease （HD） is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused ...BACKGROUND： Huntington＇s Disease （HD） is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors （NMDARs） has been shown to have a key role in the neuropathogenesis of liD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell- survival activity of GluN2A-NMDARs. OBJECTIVE： This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target. METHODS： A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including ＂Huntington＇s Disease,＂ ＂excitotoxicity,＂ ＂NMDAR＂ and ＂therapeutics.＂ RESULTS： A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs. CONCLUSION： The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.展开更多
Objective To investigate the effects of NR1 subunit on the initiation and development of seizures and protection of cortical neurons from excitotoxicity by using antisense oligodeoxynucleotides (ODN) to NR1 in vivo ...Objective To investigate the effects of NR1 subunit on the initiation and development of seizures and protection of cortical neurons from excitotoxicity by using antisense oligodeoxynucleotides (ODN) to NR1 in vivo and in vitro. Methods Intracerebroventricular injection, temporal cortex slices discharge, cerebral cortical neuronal culture, induction of neurotoxicity and MK 801 binding were used in this study. Results After an antisense ODN for NR1 was administered intracerebroventricularly (i.c.v. 100 μg in 10 μl) once daily, for three days in genetically epilepsy prone rats (GEPR, P77PMC), the animals did not develop any clonic and tonic convulsions and their seizure scores were significantly lower compared to the control groups. The frequency and amplitude of early seizure like events (SLEs) and late reccurrent discharges (LRD), induced by lowering Mg 2+ , were reduced in entorhinal cortex (EC) of the temporal cortex slice treated by antisense ODNs. Pretreatment with antisense ODN (2 μM) protected more than 52% of glutamate sensitive neurons and reduced the MK 801 binding to 50% in cultured cerebral cortical neurons. Conclusions N methy D aspartate receptors(NMDAR), specifically the NR1 subunit, may participate and play important roles in the initiation and propagation of epilepsy in the P77PMC rat.展开更多
基金supported by thegrants from National Natural Science Foundation of China(No. 30870790)Shanghai Science and Technology Commis-sion (No. 06DZ19003)in part by National Basic ResearchDevelopment Program (973) of China (No. 2009CB918402)
文摘Objective To investigate the mechanisms of excitotoxic effects of glutamate on human neuroblastoma SH-SY5Y cells. Methods SH-SY5Y cell viability was measured by MTT assay. Other damaged profile was detected by lactate dehydrogenase （LDH） release and by 4＇, 6-diamidino-2-phenylindole （DAPI） staining. The cytosolic calcium concentration was tested by calcium influx assay. The glutamate-induced oxidative stress was analyzed by cytosolic glutathione assay, superoxide dismutase （SOD） assay and extracellular malondialdehyde （MDA） assay. Results Glutamate treatment caused damage in SH- SY5Y cells, including the decrease of cell viability, the increase of LDH release and the alterations of morphological structures. Furthermore, the concentration of cytoplasmic calcium in SH-SY5Y cells was not changed within 20 min following glutamate treatment, while cytosolic calcium concentration significantly increased within 24 h after glutamate treatment, which could not be inhibited by MK801, an antagonist of NMDA receptors, or by LY341495, an antagonist of metabotropic glutamate receptors. On the other hand, oxidative damage was observed in SH-SY5Y cells treated with glutamate, including decreases in glutathione content and SOD activity, and elevation of MDA level, all of which could be alleviated by an antioxidant Tanshinone IIA （Tan IIA, a major active ingredient from a Chinese plant Salvia Miltiorrhiza Bge）. Conclusion Glutamate exerts toxicity in human neuroblastoma SH-SY5Y cells possibly through oxidative damage, not through calcium homeostasis destruction mediated by NMDA receptors.
文摘Objective To investigate a possibility of repairing damaged brain by intracerebroventricular transplantation of neural stem cells （NSCs） in the adult mice subjected to glutamate-induced excitotoxic injury. Methods Mouse NSCs were isolated from the brains of embryos at 15-day postcoitum （dpc）. The expression of nestin, a special antigen for NSC, was detected by immunocytochemistry. Immunofluorescence staining was carried out to observe the survival and location of transplanted NSCs. The animals in the MSG＋NSCs group received intracerebroventricular transplantation of NSCs （approximately 1.0×10^5 cells） separately on day 1 and day 10 after 10-d MSG exposure （4.0 g/kg per day）. The mice in control and MSG groups received intracerebroventricular injection of Dulbecco＇s minimum essential medium （DMEM） instead of NSCs. On day 11 after the last NSC transplantation, the test of Y-maze discrimination learning was performed, and then the histopathology of the animal brains was studied to analyze the MSG-induced functional and morphological changes of brain and the effects of intracerebroventricular transplantation of NSCs on the brain repair. Results The isolated cells were Nestin-positive. The grafted NSCs in the host brain were region-specifically survived at 10-d post-transplantation. Intracerebroventricular transplantation of NSCs obviously facilitated the brain recovery from glutamate-induced behavioral disturbances and histopathological impairs in adult mice. Conclusion Intracerebroventricular transplantation of NSCs may be feasible in repairing diseased or damaged brain tissue.
基金National Natural Science Foundation of China (No.81000380H1204)Natural Science Foundation of Hubei Province,China (No.2008CDA053)Scientific Research Fund of the Ministry of Health,Hubei Province,China (No.QJX2010-53)
文摘AIM: To investigate whether bis (7)-tacrine, a multifunctional drug, inhibits N-methyl-D-aspartate (NMDA) -activated current in retinal ganglion cells (RGC) and provides neuroprotection against retinal cell damage. METHODS: Purified RGC cultures were obtained from retinas of 1-3 days old Sprague-Dawley (SD) rats, following a two-step immunopanning procedure. After 7 days of cultivation, the inhibition of NMDA-activated current by bis(7) -tacrine was measured by using patch-clamp recording techniques. In animal experiments, RGCs were damaged after intravitreal injection of NMDA (5 mu L, 40nmol) in adult rats. Bis (7)-tacrine(0.05, 0.1, 0.2mg/kg) or memantine(20mg/kg) was intraperitoneal administered to the rats fifteen minutes before intravitreally injection of NMDA. RGC damage was analyzed by histologic techniques, TUNEL and retrograde labeling techniques. RESULTS: Whole-cell patch-clamp recordings demonstrated that NMDA (30 mu mol/L) resulted in approximately -50 pA inward currents that were blocked by bis (7)-tacrine (1 mu mol/L). Histological examination and retrograde labeling analysis revealed that bis (7)-tacrine induced a significant neuroprotective effect against NMDA-induced cell damage 7 days after NMDA injection. TUNEL staining showed that pretreatment with bis(7)-tacrine was effective in ameliorating NMDA-induced apoptotic cell loss in the retinal ganglion cell layer 18 hours after injection. CONCLUSION: Bis (7)-tacrine possesses remarkable neuroprotective activities against retinal excitotoxicity through inhibition of NMDA receptors.
基金supported by the National Natural Science Foundation of China,Nos.81974132,81770927Hunan Provincial Health Commission,No.20220702839+1 种基金the Natural Science Foundation of Hunan Province of China,No.2022JJ30076National Key R&D Program of China,No.2021YFA1101202(all to WS)。
文摘Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.
文摘Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,
基金supported by the National Key R&D Program of China,No.2016YFC1201800(to JFH)the Key Research and Development Program of Hunan Province,Nos.2018SK2090(to JFH),2022SK2079(to JFH)+2 种基金the Natural Science Foundation of Hu nan Province,No.2021JJ30891(to DC)the Human Resource Bank Program of Hunan Province,No.2020TP3003(to JFH)the School-Enterprise Joint Program of Central South University,No.2021XQLH092(to TQD)。
文摘Adipose mesenchymal stem cells(ADSCs)have protective effects against glutamate-induced excitotoxicity,but ADSCs are limited in use for treatment of optic nerve injury.Studies have shown that the extracellular vesicles(EVs)secreted by ADSCs(ADSC-EVs)not only have the function of ADSCs,but also have unique advantages including non-immunogenicity,low probability of abnormal growth,and easy access to target cells.In the present study,we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography.In addition,R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium,downregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor(AMPAR)subunit GluA2,and phosphorylation of GluA2 and protein kinase C alpha in vitro.A protein kinase C alpha agonist,12-O-tetradecanoylphorbol 13-acetate,inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells.These findings suggest that ADSCEVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.
基金Supported by National Natural Science Foundation of China (No.81400398)
文摘AIM： To explore the more suitable concentration of glutamate or N-methyl-D-aspartic acid（NMDA） for intravitreal injection to establish a rat model of retinal neurodegeneration. METHODS： We injected different doses of glutamate（20 or 50 nmol） or NMDA（40 nmol） into the vitreous chambers of rats, then measured the concentration of glutamate and retinal thickness, quantified apoptotic cells and determined the degree of tau hyperphosphorylation at different time points. T-test was used for comparison of two groups. One-way ANOVA and Turkey＇s multiple comparisons test were used for comparisons of different groups, and P values below 0.05 were considered statistically significant.RESULTS： The glutamate level in the rats treated with 50 nmol of glutamate was twice that of the control group and persisted two weeks. Seven days after intravitreal injection of 50 nmol of glutamate, three parameters [inner retinal thickness（IRT）, retinal thickness（RT） and ganglion cell layer（GCL） cell number] were reduced significantly. Furthermore, numerous TUNEL-positive cells were observed in the GCL one day after intravitreal injection of 50 nmol of glutamate, the expression of the apoptosisrelated factor cleaved casepase-3 was markedly increased compared with the expression levels in the other treatment groups, and the expression levels of tau s396 and tau s404 were significantly increased compared with those in the control group.CONCLUSION： This study demonstrates that the intravitreal injection of 50 nmol of glutamate can establish the more effective retinal neurodegeneration animal model relative to other treatment groups.
基金supported by the Scientific and Technical Innovation Fund of Shanxi Medical University,No.01200802Shanxi Province Foundation for Returnees,No.2007-43
文摘Previous studies have shown that mitogen-activated protein kinase （MAPK） signaling pathways are involved in N-methyI-D-aspartate （NMDA）-mediated excitotoxicity. However, a systematic observation or analysis of the role of these various MAPK pathways in excitotoxicity processes does not exist. The present study further evaluated the role and contribution of three MAPK pathways extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK in an NMDA-mediated excitotoxicity model using MAPK^specific inhibitor. Results demonstrated that c-Jun N-terminal kinase inhibitor SP600125 and/or p38 MAPK inhibitor SB203580 inhibited NMDA-induced reduction in cell viability, as well as reduced NMDA-induced lactate dehydrogenase leakage and reactive oxygen species production. However, PD98059, an inhibitor of extracellular signal-regulated kinase, did not influence this model. Results demonstrated an involvement of c-Jun N-terminal kinase and p38 MAPK, but not extracellular signal-regulated kinase, in NMDA-mediated excitotoxicity in cortical neurons.
基金supported by grants from National Natural Science Foundation of China(No.30872858)Research Fund for Doctoral Program of Higher Education of China(No.200800250006)Beijing Municipal Natural Science Foundation of China(No.7082024)
文摘Glutamate（Glu） is the major afferent excitatory neurotransmitter in the auditory system, and excessive Glu may play an important role in cochlear dysfunction. It is unclear how excessive Glu plays roles in cochlear dysfunction in cochlear organotypic cultures. In this study neonatal rat cochlear organotypic cultures were prepared, and then the cochlear tissues were incubated with a new medium containing specific concentrations of Glu（0.1, 0.5, 1, 10 or 20 mmol/L） for 24 h, or incubated with the medium containing a concentration of 20 mmol/L Glu for 6, 12, 24 or 72 h, respectively. It was found that when the cochlear tissues were cultured for 24 h, the inner hair cells（IHCs） were damaged at the concentration of 0.5 mmol/L Glu, and with the increases of the concentrations, the injury was gradually aggravated, and 20 mmol/L Glu resulted in the significant loss of IHCs. In the 20 mmol/L Glu groups, the stereocilia bundles were missing or disarrayed on a few IHCs after culture for 6 h and the damage effect was time-dependent. The missing of IHCs was more significant in the basal turn of the cochlea than in the middle turn of the cochlea under the same concentration of Glu exposure. These results suggest that excessive exogenous Glu affects the morphology of IHCs, but not affects the outer hair cells（OHCs） in cochlear organotypic cultures, and the excitotoxic effects are different on IHCs of different parts of the cochlea under the same concentration of Glu exposure.
文摘Recent studies have demonstrated that ferulic acid[3-（4-hydroxy-3-methoxyphenyl）-2-propenoic acid]and sodium ferulate produce protective effects against glutamate-induced neurotoxicity in adult mice.Danshensu（β-3,4-dihydroxyphenyl-lactic acid）has a similar molecular structure and pharmacological action to caffeic acid.This study aimed to validate the protection conferred by Danshensu against excitotoxic effects of maternal intragastric administration of monosodium glutamate at late stages of pregnancy in the developing mouse fetal brain.Behavioral tests,as well as histopathological and immunohistochemical examination of hippocampi were performed in filial mice.Results revealed that maternal intragastric administration of excessive monosodium glutamate（1.0,2.0,4.0 g/kg body weight）at a late stage of pregnancy resulted in a series of behavioral disorders（hyperactivity,lesions of learning and memory,and disturbance in cooperation of movement ability under high-altitude stress）,histopathological impairment（neuronal edema,degeneration,necrosis,and hyperplasia）and molecular cellular biological changes（upregulated expression of N-methyI-D-aspartate receptor type 1 and neuropeptide Y in the hippocampal region of the brain of the filial mice from mothers treated with monosodium glutamate）.Simultaneous administration of sodium Danshensu partially reversed the effects of monosodium glutamate on the above mentioned phenomena.These findings indicate that sodium Danshensu exhibits obvious protective effects on the excitotoxicity of monosodium glutamate.
基金supported by grants from FAPERJ,CNPq(INCT-INNT),CAPES and PROLAB LARC/IBRO/CNPq
文摘The retina is a multilayered tissue that develops following a central-to-peripheral gradient. Its structure derives from multipotent precursors, as shown through clonal analysis of retinal cell lineage. These progenitors generate diverse cell types, controlled by complex influences of intrinsic and extrinsic factors （Hatakevama and Kagevama, 2004）.
基金supported by University of Florence RICATEN 2023 to EC.Grant/Award Numbers 58514_InternazionalizzazioneUniversity of Florence,to EC.Parkinson’s UK,Grant/Award Number:H-0902 to AJGWellcome Trust,Grant/Award Number:0926/Z/10/Z to AJG。
文摘During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.
文摘Objective: Our previous studies have revealed that ferulic acid (FA) and sodium ferulate (SF) show significant protective effect on excitotoxicity, the present study was conducted to compare its potential favorable effects of maternal,newborn,and both maternal and newborn intraperitoneal (ip) injection of SF on repair following excitotoxic neuronal damages induced by monosodium glutamate (MSG). Methods: The maternal mice were assigned randomly into seven groups (n = 10 animals in each group): control, 3SF, 20SF, 23SF, MSG, MSG + 3SF, MSG + 20SF, MSG + 23SF groups. The mice at 17 days of pregnancy were treated with or without MSG (2.0 g/kg body weight, ig, once) or/and SF (40 mg/kg body weight, ip), and their offerings treated with or without SF. And then their filial behaviors and hippocampal histopathology were studied. Results: The results showed that maternal, newborn, and both maternal and newborn administration of SF facilitated their filial brain repair, and attenuated the behavioral disorders and histopathological damages of their filial mice in MSG + 3SF, MSG + 20SF, and MSG + 23SF groups in varying degrees. However, the best effects were detected in the filial mice in MSG + 23SF group. Conclusion: Both maternal and newborn administration of SF is conducive to the filial neuronal repair following excitotoxic damages induced by glutamate.
基金supported by the National Natural Science Foundation of China,Nos.82301093(to QC)and 22334004(to HY)the Fuzhou University Fund for Testing Precious Equipment,No.2025T038(to QC)。
文摘The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular recanalization treatments such as thrombolysis and mechanical thrombectomy have achieved some success,reperfusion injury remains a significant contributor to the exacerbation of brain injury.This emphasizes the need for developing neuroprotective strategies to mitigate this type of injury.The purpose of this review was to examine the application of nanotechnology in the treatment of ischemic stroke,covering research progress in nanoparticlebased drug delivery,targeted therapy,and antioxidant and anti-inflammatory applications.Nanobased drug delivery systems offer several advantages compared to traditional therapies,including enhanced blood–brain barrier penetration,prolonged drug circulation time,improved drug stability,and targeted delivery.For example,inorganic nanoparticles,such as those based on CeO_(2),have been widely studied for their strong antioxidant capabilities.Biomimetic nanoparticles,such as those coated with cell membranes,have garnered significant attention owing to their excellent biocompatibility and targeting abilities.Nanoparticles can be used to deliver a wide range of neuroprotective agents,such as antioxidants(e.g.,edaravone),anti-inflammatory drugs(e.g.,curcumin),and neurotrophic factors.Nanotechnology significantly enhances the efficacy of these drugs while minimizing adverse reactions.Although nanotechnology has demonstrated great potential in animal studies,its clinical application still faces several challenges,including the long-term safety of nanoparticles,the feasibility of large-scale production,quality control,and the ability to predict therapeutic effects in humans.In summary,nanotechnology holds significant promise for the treatment of ischemic stroke.Future research should focus on further exploring the mechanisms of action of nanoparticles,developing multifunctional nanoparticles,and validating their safety and efficacy through rigorous clinical trials.Moreover,interdisciplinary collaboration is essential for advancing the use of nanotechnology in stroke treatment.
文摘Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.
基金This work was done under the auspice of Consejo Nacional de Ciencia y Tecnología(CONACyT,protocol approval number 240817)of Dirección General de Asuntos del Personal Académico(DGAPA),UNAM(protocol approval number IN204516).RLG is recipient of a CONACyT doctoral scholarship.
文摘Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorders.Polyphenols,such as quercetin and resveratrol,are plant-derived compounds that activate sirtuins(SIRTs)and have shown promising results in some models of neuronal death,although their effects have been scarcely tested in models of motor neuron degeneration.Methods:In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)into the rat spinal cord tissue.Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days.Then,animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures.Results:We found that the chronic infusion of AMPA[1 mM]caused a progressive motor neuron degeneration,accompanied by astrogliosis and microgliosis,and motor deficits and paralysis of the rear limbs.Quercetin infusion ameliorated AMPA-induced paralysis,rescued motor neurons,and prevented both astrogliosis and microgliosis,and these protective effects were prevented by EX527,a very selective SIRT1 inhibitor.In contrast,neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration,albeit both reduced gliosis.Conclusions:These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism,and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.
文摘Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders.The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders.The dysregulation of glutamate signaling,leading to excitotoxicity and neuronal cell death,has been a focal point in understanding the underlying mechanisms of these conditions.This has prompted a paradigm shift in neuroprotection research,with a growing emphasis on targeting ionotropic glutamate receptors(iGluRs)to restore glutamatergic homeostasis.This review provides a comprehensive overview of recent advancements in the field of iGluR-targeted neuroprotection.We further investigate the implications of glutamate dysregulation in the central nervous system(CNS)disorders,highlighting the complex interplay between excitotoxicity and neuroprotection.We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage,emphasizing the need for innovative therapeutic approaches.This review provides an extensive survey of the burgeoning field of iGluR-targeted neuroprotection.It showcases the significant potential of a wide array of compounds,encompassing both natural and synthetic agents,to modulate iGluRs and ameliorate excitotoxicity and oxidative stress-induced neuronal damage.These compounds have demonstrated impressive neuroprotective effects in diverse experimental models,from glutamate-induced toxicity to traumatic brain injuries.We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation,heralding a promising era in neuroprotection and CNs disorder management.
文摘BACKGROUND： Huntington＇s Disease （HD） is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors （NMDARs） has been shown to have a key role in the neuropathogenesis of liD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell- survival activity of GluN2A-NMDARs. OBJECTIVE： This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target. METHODS： A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including ＂Huntington＇s Disease,＂ ＂excitotoxicity,＂ ＂NMDAR＂ and ＂therapeutics.＂ RESULTS： A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs. CONCLUSION： The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.
文摘Objective To investigate the effects of NR1 subunit on the initiation and development of seizures and protection of cortical neurons from excitotoxicity by using antisense oligodeoxynucleotides (ODN) to NR1 in vivo and in vitro. Methods Intracerebroventricular injection, temporal cortex slices discharge, cerebral cortical neuronal culture, induction of neurotoxicity and MK 801 binding were used in this study. Results After an antisense ODN for NR1 was administered intracerebroventricularly (i.c.v. 100 μg in 10 μl) once daily, for three days in genetically epilepsy prone rats (GEPR, P77PMC), the animals did not develop any clonic and tonic convulsions and their seizure scores were significantly lower compared to the control groups. The frequency and amplitude of early seizure like events (SLEs) and late reccurrent discharges (LRD), induced by lowering Mg 2+ , were reduced in entorhinal cortex (EC) of the temporal cortex slice treated by antisense ODNs. Pretreatment with antisense ODN (2 μM) protected more than 52% of glutamate sensitive neurons and reduced the MK 801 binding to 50% in cultured cerebral cortical neurons. Conclusions N methy D aspartate receptors(NMDAR), specifically the NR1 subunit, may participate and play important roles in the initiation and propagation of epilepsy in the P77PMC rat.
