Ethanol, stroke, brain damage, and excitotoxicity.
The N-methyl-d-aspartate (NMDA)-glutamate receptor could contribute to stroke, trauma, and alcohol-induced brain damage through activation of nitric oxide formation and excitotoxicity. In rat primary cortical cultures NMDA was more potent at activating nitric oxide formation than triggering excitotoxicity. Ethanol dose dependently inhibited both responses. In contrast, treatment of neuronal cultures with ethanol (100 mM) for 4 days significantly increased NMDA stimulated nitric oxide formation and excitotoxicity. These findings suggest that ethanol acutely inhibits but chronically causes supersensitivity to NMDA-induced excitotoxicity in neuronal cultures. To investigate ethanol's interaction with stroke induced damage models of global cerebral ischemia were studied. Transient global ischemia resulted in a loss of hippocampal CA1 pyramidal neurons over a 3- to 5-day period. Determinations of the NMDA receptor ligand binding stoichiometry or postischemic receptor binding changes did not show differences between neurons that undergo delayed neuronal death following ischemia and those that show no toxicity, for example, CA1 and dentate gyrus, respectively. Acute ethanol (3 g/kg) was found to protect against ischemia-induced CA1 hippocampal damage by lowering body temperature, but not under temperature controled conditions. These studies indicate that the factors contributing to stroke-induced brain damage are complex, although they are consistent with chronic ethanol increasing stroke-induced brain damage by increasing NMDA excitotoxicity.
Crews
F T
FT
Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 27599-7178, USA.
Steck
J C
JC
Chandler
L J
LJ
Yu
C J
CJ
Day
A
A
D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity*; D002561:Cerebrovascular Disorders / Q000473:pathology*; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase