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1.
Effects of ciliary neurotrophic factor on excitotoxicity and calcium-ionophore A23187-induced cell death in cultured embryonic striatal neurons 总被引:2,自引:0,他引:2
Ciliary neurotrophic factor (CNTF) has a protective effect on the striatum in animal models of Huntington's disease. However, the mechanism through which it exerts its effect is not clear. In this study, we show that there is a concentration-dependent direct protective effect of CNTF against N-methyl-D-aspartate-mediated excitotoxicity on striatal neurons in vitro. The CNTF has to be added more than half an hour before the insult for the effect to occur and its effect is eliminated by the presence of the protein synthesis inhibitor cycloheximide. This suggests that the protective mechanism of CNTF does not involve acute interference with the glutamate receptors, but probably requires gene/protein expression. We have also shown that the effect of CNTF against glutamate-induced excitotoxicity is dependent on the concentration of glutamate with a protective effect more evident at a low grade excitotoxic insult. Finally, we saw no effect of CNTF on calcium ionophore A23187-induced toxicity in striatal cultures, indicating that the growth factor does not promote survival by enhancing general defenses against raised intracellular levels of calcium. 相似文献
2.
Ferrarese C Zoia C Pecora N Piolti R Frigo M Bianchi G Sala G Begni B Riva R Frattola L 《Journal of neural transmission (Vienna, Austria : 1996)》1999,106(7-8):685-692
Summary. Defects in mitochondrial enzymes have been found not only in substantia nigra, but also in platelets from Parkinson's Disease
(PD) patients, suggesting a systemic impairment of energy metabolism. Since platelets present an energy-dependent glutamate
uptake similar to that described in central nervous system, glutamate uptake was determined in platelets from 34 PD patients
and 21 age-related normal controls, as Na+-dependent [3H]glutamate influx; glutamate level was also analyzed by reverse-phase HPLC. A 50% reduction of glutamate uptake (p < 0.001)
was observed in idiopathic PD patients, respect to controls and secondary parkinsonian syndromes. The decrease correlated
with the severity of PD, measured by the UPDRS (r = −0.54; P < 0.05). Glutamate level was increased in platelets of PD patients,
but was not correlated to the uptake decrease. Both phoenomena may be explained by the modifications of mitochondrial enzymes
described in platelets, which could be used as a peripheral model of glutamatergic function in PD.
Received October 7, 1998; accepted January 7, 1999 相似文献
3.
Glutamate Toxicity: An Experimental and Theoretical Analysis 总被引:2,自引:0,他引:2
In slices of 8-day-old rat cerebellum, the lowest concentration of glutamate that induced toxicity (30 min exposure; 90 min recovery) was 100 microM, but the damage only occurred in the outermost regions. As the concentration was raised, the band of necrosis became progressively deeper until, at 3 mM, it was uniform across the slice thickness. At a test concentration of 300 microM, the width of the necrotic band did not change when either the exposure time or the recovery period was varied between 30 min and 3 h. These results are predicted by a theoretical model in which the diffusion of glutamate into brain tissue is countered by cellular uptake of the amino acid, and they argue against the idea that glutamate toxicity is inherently self-propagating. When slices were examined immediately after exposure (300 microM), a prominent swelling of glial cells was present at the slice surface. Swelling per se did not appear to compromise their uptake function, and the model predicts that cellular swelling, by reducing the rate of diffusion of glutamate, protects against glutamate toxicity. The damage produced by 3 mM glutamate, which was primarily exerted against granule cells, was prevented by N-methyl-d-aspartate (NMDA) receptor blockade, whereas antagonists acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors were ineffective. Under conditions of energy deprivation, the neurotoxic potency of glutamate was markedly enhanced and a normally non-toxic concentration (30 microM) became maximally toxic towards granule cells. Dark vacuolar degeneration of Purkinje cells was also present, and this could be inhibited by blocking AMPA receptors. The results and theoretical analysis suggest that intact brain tissue is remarkably resistant to glutamate toxicity, chiefly because of the formidable properties of the uptake system. However, under special circumstances, glutamate can become a potent neurotoxin and its toxicity can then involve both NMDA and AMPA receptors. 相似文献
4.
神经营养因子对缺血性脑损伤的影响及其药物调节 总被引:2,自引:2,他引:2
营养因子是一类对神经系统起营养支持作用的蛋白质 ,当神经细胞受损伤时 ,可引起不同种类的神经营养因子释放 ,从而参与脑损伤的内源性保护过程。外源性施用神经营养因子可保护神经组织免受损害的实验结果也支持上述观点。因此 ,利用药物等手段诱导它们适时适量地释放 ,可能是治疗缺血性脑损伤的新靶向 相似文献
5.
兴奋性氨基酸与青光眼 总被引:5,自引:3,他引:5
近年来随着对青光眼性视神经病变机制的深入研究,已证实兴奋性氨基酸与青光眼视网膜神经节细胞凋亡密切相关。21世纪青光眼的治疗模式正从传统的单纯降眼压向降眼压的同时从其他途径进一步加强神经保护转变,基础实验及部分临床研究证实干扰兴奋性氨基酸产生神经毒性的各环节均对神经元有保护作用,由此可以推测通过对兴奋性氨基酸的研究有望实现青光眼治疗史上的重大突破。 相似文献
6.
《Expert opinion on investigational drugs》2013,22(10):1343-1364
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurons. The mechanisms and processes responsible for the selective loss of motor neurons are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by ~ 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease. 相似文献
7.
Gael Barthet Julie Dunys Zhiping Shao Zhao XuanYimin Ren Jindong XuAnastasios Georgakopoulos Junichi ShioiNikolaos K. Robakis 《Neurobiology of aging》2013
Activation of EphB receptors by ephrinB (efnB) ligands on neuronal cell surface regulates important functions, including neurite outgrowth, axonal guidance, and synaptic plasticity. Here, we show that efnB rescues primary cortical neuronal cultures from necrotic cell death induced by glutamate excitotoxicity and that this function depends on EphB receptors. Importantly, the neuroprotective function of the efnB/EphB system depends on presenilin 1 (PS1), a protein that plays crucial roles in Alzheimer's disease (AD) neurodegeneration. Furthermore, absence of one PS1 allele results in significantly decreased neuroprotection, indicating that both PS1 alleles are necessary for full expression of the neuroprotective activity of the efnB/EphB system. We also show that the ability of brain-derived neurotrophic factor (BDNF) to protect neuronal cultures from glutamate-induced cell death depends on PS1. Neuroprotective functions of both efnB and BDNF, however, were independent of γ-secretase activity. Absence of PS1 decreases cell surface expression of neuronal TrkB and EphB2 without affecting total cellular levels of the receptors. Furthermore, PS1-knockout neurons show defective ligand-dependent internalization and decreased ligand-induced degradation of TrkB and Eph receptors. Our data show that PS1 mediates the neuroprotective activities of efnB and BDNF against excitotoxicity and regulates surface expression and ligand-induced metabolism of their cognate receptors. Together, our observations indicate that PS1 promotes neuronal survival by regulating neuroprotective functions of ligand-receptor systems. 相似文献
8.
Mário Sérgio Lima de Lavor Nancy Scardua Binda Fabíola Bono Fukushima Fátima Maria Caetano Caldeira Juliana Figueira da Silva Carla Maria Osório Silva Karen Maciel de Oliveira Bernardo de Caro Martins Bruno Benetti Junta Torres Isabel Rodrigues Rosado Renato Santiago Gomez Marcus Vinícius Gomez Eliane Gon?alves de Melo 《International journal of clinical and experimental pathology》2015,8(9):9941-9949
This work aimed at determining the ideal ischemia time in an in vitro ischemia-reperfusion model of spinal cord injury. Rat spinal cord slices were prepared and then exposed or not to oxygen deprivation and low glucose (ODLG) for 30, 45, 60, 75 and 90 minutes. Cell viability was assessed by triphenyltetrazolium (TTC), lactate dehydrogenase (LDH) release, and fluorochrome dyes specific for cell dead (ethidium homodimer) using the apotome system. Glutamate release was enzymatically measured by a fluorescent method. Gene expression of apoptotic factors was assessed by real time RT-PCR. Whereas spinal cord slices exposed to ODLG exhibited mild increase in fluorescence for 30 minutes after the insult, the 45, 60, 75 and 90 minutes caused a 2-fold increase. ODLG exposure for 45, 60, 75 or 90 minutes, glutamate and LDH release were significantly elevated. nNOS mRNA expression was overexpressed for 45 minutes and moderately increased for 60 minutes in ODLG groups. Bax/bcl-xl ratio, caspase 9 and caspase 3 mRNA expressions were significantly increased for 45 minutes of ODLG, but not for 30, 60, 75 and 90 minutes. Results showed that cell viability reduction in the spinal cord was dependent on ischemic time, resulting in glutamate and LDH release. ODLG for 45 minutes was adequate for gene expression evaluation of proteins and proteases involved in apoptosis pathways. 相似文献
9.
10.
Hemiplegic migraine (HM) is characterized by motor weakness and at least one other aura symptom or sign that is fully reversible within 24 hours. While prolonged neurological impairment lasting weeks has been observed, persistent attack-related neurological deficits have not been described. This case illustrates the potential for permanent neurological deficits to occur as a sequelae of HM in the absence of infarction, and highlights potentially important pathophysiological and treatment implications. 相似文献