Vicious cycle involving na+ channels, glutamate release, and nmda receptors mediates delayed neurodegeneration through nitric oxide formation
TLDR
Investigation of an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief challenge with the glutamate receptor agonist NMDA suggests that Na+ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegenersation.Abstract:
The mechanisms by which neurons die after cerebral ischemia and related conditions in vivo are unclear, but they are thought to involve voltage-dependent Na+ channels, glutamate receptors, and nitric oxide (NO) formation because selective inhibition of each provides neuroprotection. It is not known precisely what their roles are, nor whether they interact within a single cascade or in parallel pathways. These questions were investigated using an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief (5 min) challenge with the glutamate receptor agonist NMDA. Unexpectedly, NO was generated continuously by the cultures for up to 16 hr after the NMDA exposure. Neuronal death followed the same general time course except that its start was delayed by ∼4 hr. Application of the NO synthase inhibitor nitroarginine after, but not during, the NMDA exposure inhibited NO formation and protected against delayed neuronal death. Blockade of NMDA receptors or of voltage-sensitive Na+ channels [with tetrodotoxin (TTX)] during the postexposure period also inhibited both NO formation and cell death. The NMDA exposure resulted in a selective accumulation of glutamate in the culture medium during the period preceding cell death. This glutamate release could be inhibited by NMDA antagonism or by TTX, but not by nitroarginine. These data suggest that Na+ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegeneration. At the core of the mechanism is a vicious cycle in which NMDA receptor stimulation causes activation of TTX-sensitive Na+ channels, leading to glutamate release and further NMDA receptor stimulation. The output of the cycle is an enduring production of NO from neuronal sources, and this is responsible for delayed neuronal death. The same neurons, however, could be induced to undergo more rapid NMDA receptor-dependent death that required neither TTX-sensitive Na+ channels nor NO.read more
Citations
More filters
Journal ArticleDOI
Ischemic Cell Death in Brain Neurons
TL;DR: A major unifying thread of the review is a consideration of how the changes occurring during and after ischemia conspire to produce damaging levels of free radicals and peroxynitrite to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process.
Journal ArticleDOI
Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.
TL;DR: Mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD are discussed andNMDA receptor antagonists have potential for the therapeutic amelioration of AD.
Journal ArticleDOI
Nitric oxide and mitochondrial respiration.
TL;DR: In this article, it was shown that low (nanomolar) concentrations of NO specifically inhibit cytochrome oxidase in competition with oxygen, and this inhibition is fully reversible when NO is removed.
Journal ArticleDOI
Chronic ethanol consumption:from neuroadaptation to neurodegeneration
Fabio Fadda,Zvani L. Rossetti +1 more
TL;DR: Evidence suggests a link between the neuroadaptive mechanisms underlying the development of ethanol dependence and those underlying the functional and structural alterations induced by chronic ethanol.
Journal ArticleDOI
The role of nitric oxide in multiple sclerosis.
Kenneth Smith,Hans Lassmann +1 more
TL;DR: Alternative approaches based on the inhibition of superoxide production, partial sodium-channel blockade, or the replacement of lost immunomodulatory function, may prove beneficial in patients with MS.
References
More filters
Journal ArticleDOI
Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays
TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
Journal Article
Nitric oxide: physiology, pathophysiology, and pharmacology
Journal ArticleDOI
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
TL;DR: NO released from endothelial cells is indistinguishable from EDRF in terms of biological activity, stability, and susceptibility to an inhibitor and to a potentiator.
Journal ArticleDOI
Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.
TL;DR: It is proposed that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO under pathological conditions by preventing the formation of peroxynitrite.
Journal ArticleDOI
Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.
TL;DR: It is reported here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF that accounts for the cGMP responses that take place following NMDA receptor activation.
Related Papers (5)
The role of glutamate neurotoxicity in hypoxic- ischemic neuronal death
Dennis W. Choi,Steven M. Rothman +1 more