NMDA-mediated toxicity to striatal neurons is not reversed by 7-nitroindazole, an inhibitor of neuronal nitric oxide synthase.
L-glutamate itself and compounds activating glutamate receptor subtypes such as N-methyl-D-aspartate (NMDA) can produce excitotoxic lesions similar to neuronal cell damage following ischemia, traumatic brain injury or as seen in human neurodegenerative disorders. Competitive and non-competitive NMDA-receptor antagonists have neuroprotective properties in a number of in-vitro and in-vivo models for these disorders. The discovery of nitric oxide (NO) in the central nervous system (CNS) and the demonstration of the link between glutamate receptor activation and NO formation led to the hypothesis that NMDA toxicity may be mediated by NO because of its ability to promote free radical generation. Three isoforms of nitric oxide synthase (NOS) have been described, one of which is expressed constitutively in neuronal tissues (nNOS) and is perferentially inhibited by 7-nitroindazole (7-NI). One day after intrastriatal injection of NMDA, systemic pretreatment of rats with 7-NI had no effect on lesion volumes. It is concluded that formation of NO subsequent to NMDA receptor stimulation is not critically involved in excitotoxicity seen in this model.
Löschmann
P A
PA
Department of Neurology, University of Tübingen, Federal Republic of Germany.
Eblen
F
F
Wüllner
U
U
Klockgether
T
T
D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole