Antagonism by Ng-nitro-l-arginine ofl-glutamate-induced neurotoxicity in cultured neonatal rat cortical neurons. Prolonged application enhances neuroprotective efficacy

Vigé, Xavier; Carreau, Alexandra; Scatton, B.; Nowicki, Jean-Pierre

doi:10.1016/0306-4522(93)90306-z

Cited by 49 publications

(13 citation statements)

References 38 publications

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“…Our evidence obtained using a primary culture model shows that key phenomenological properties of the pathogenesis of neuronal death in vivo, namely, a dependence on Na ϩ channels, NMDA receptors, and nNOS, can be incorporated into a mechanistic sequence that explicitly defines the roles of these proteins and that implicitly identifies several specific questions that can now be subjected to direct experimental tests. Although the experiments were carried out using cultures of striatum, some of the features of the pathological mechanism we have elucidated have been noted previously in studies of other brain areas, including cerebral cortex and hippocampus (Dawson et al, 1993;Vigé et al, 1993;Dubinsky et al, 1995), indicating that our results may be more broadly applicable. The scheme suggested by our findings is shown in Figure 6, the main points of which are as follows.…”

Section: Discussionmentioning

confidence: 70%

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

1996

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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 ϩ 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 ϳ4 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 ϩ 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 ϩ 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 ϩ 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 ϩ channels nor NO.

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Section: Discussionmentioning

confidence: 70%

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

1996

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“…Subsequent studies showed that treatment of cultures with low doses of quisqualate, which preferentially kills nitric oxide synthase containing neurons, blocked glutamate neurotoxicity in cultured cortical and striatal neurons (Dawson et al, 1993). These results have been replicated in some studies (Izumi et al, 1992;VigC et al, 1993) but not in others (Demerle-Pallardy et al, 1991;Pauwels and Leysen, 1992;Hewett et al, 1993;Regan et al, 1993;Zinkand et al, 1993;Garthwaite and Garthwaite, 1994) Results in vivo were also inconsistent in protecting hippocampal neurons from NMDA neurotoxicity (Haberny et al, 1992;Lerner-Natoli et al, 1992;Moncada et al, 1992).…”

Section: Discussionmentioning

confidence: 98%

Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo

et al. 1995

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Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. We examined the effects of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) on excitotoxic striatal lesions. 7-NI significantly attenuated lesions produced by intrastriatal injections of NMDA, but not kainic acid or alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 7-NI attenuated secondary striatal excitotoxic lesions produced by the succinate dehydrogenase inhibitor malonate, and the protection was reversed by L- arginine but not by D-arginine, 7-NI produced nearly complete protection against striatal lesions produced by systemic administration of 3-nitropropionic acid (3-NP), another succinate dehydrogenase inhibitor, 7-NI protected against malonate induced decreases in ATP, and increases in lactate, as assessed by 1H magnetic resonance spectroscopy. 7-NI had no effects on spontaneous electrophysiologic activity in the striatum in vivo, suggesting that its effects were not mediated by an interaction with excitatory amino acid receptors. 7-NI attenuated increases in hydroxyl radical, 8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. The present results implicate neuronal nitric oxide generation in the pathogenesis of both direct and secondary excitotoxic neuronal injury in vivo. As such they suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.

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“…This observation is based on the findings that blocking formation of NO using NOS inhibitors attenuates glutamate-induced neuronal death (Yamauchi et al, 1998). However, it has been shown that this effect is concentration-and time-dependent (Vigé et al, 1993). Thus, addition of 100 M N -nitro-L-arginine to the medium either 5 min before and during 500 M L-glutamate exposure for 5 min decreased the amino acid-induced neurotoxicity only by 20%.…”

Section: Excitotoxic Glutamate Injury Produces a Persistent Inward Exmentioning

confidence: 99%

Activation of a Novel Injury-Induced Calcium-Permeable Channel That Plays a Key Role in Causing Extended Neuronal Depolarization and Initiating Neuronal Death in Excitotoxic Neuronal Injury

Deshpande

Limbrick²,

Sombati³

et al. 2007

J Pharmacol Exp Ther

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Protracted elevation in intracellular calcium caused by the activation of the N-methyl-D-aspartate receptor is the main cause of glutamate excitotoxic injury in stroke. However, upon excitotoxic injury, despite the presence of calcium entry antagonists, calcium unexpectedly continues to enter the neuron, causing extended neuronal depolarization and culminating in neuronal death. This phenomenon is known as the calcium paradox of neuronal death in stroke, and it represents a major problem in developing effective therapies for the treatment of stroke. To investigate this calcium paradox and to determine the source of this unexpected calcium entry after neuronal injury, we evaluated whether glutamate excitotoxicity activates an injury-induced calcium-permeable channel responsible for conducting a calcium current that underlies neuronal death. We used a combination of whole-cell and single-channel patchclamp recordings, fluorescent calcium imaging, and neuronal cell death assays in a well characterized primary hippocampal neuronal culture model of glutamate excitotoxicity/stroke. Here, we report activation of a novel calcium-permeable channel upon excitotoxic glutamate injury that carries calcium current even in the presence of calcium entry inhibitors. Blocking this injury-induced calcium-permeable channel for a significant time period after the initial injury is still effective in preventing calcium entry, extended neuronal depolarization, and delayed neuronal death, thereby accounting for the calcium paradox. This injury-induced calcium-permeable channel represents a major source for the initial calcium entry following stroke, and it offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.Stroke is a leading cause of disability and death, yet its successful treatment is limited (Bonita et al., 2004). Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system, and it is required for neural development, synaptogenesis, and alterations in synaptic plasticity (Dingledine et al., 1999). In excessive quantities, glutamate is thought to cause the neuronal damage observed following stroke, epilepsy, and traumatic brain injury (Siesjö and Bengtsson, 1989;Delorenzo et al., 2005). Protracted elevation in intracellular calcium [Ca 2ϩ ] i caused by the activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is the main cause of excitotoxic injury in stroke (Choi, 1995;Lipton, 1999). Excitotoxic glutamate exposure causes two major, long-lasting changes in neuronal physiology. Our laboratory and others have demonstrated that glutamate exposure results in a prolonged dis-

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Antagonism by Ng-nitro-l-arginine ofl-glutamate-induced neurotoxicity in cultured neonatal rat cortical neurons. Prolonged application enhances neuroprotective efficacy

Cited by 49 publications

References 38 publications

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo

Activation of a Novel Injury-Induced Calcium-Permeable Channel That Plays a Key Role in Causing Extended Neuronal Depolarization and Initiating Neuronal Death in Excitotoxic Neuronal Injury

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Antagonism by Ng-nitro-l-arginine ofl-glutamate-induced neurotoxicity in cultured neonatal rat cortical neurons. Prolonged application enhances neuroprotective efficacy

Cited by 49 publications

References 38 publications

Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo

Activation of a Novel Injury-Induced Calcium-Permeable Channel That Plays a Key Role in Causing Extended Neuronal Depolarization and Initiating Neuronal Death in Excitotoxic Neuronal Injury

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Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

Vicious Cycle Involving Na⁺Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation