NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brain in vivo.
Effects of high and moderate affinity uncompetitive NMDA receptor antagonists (+)MK-801 and memantine on ischemic tolerance were compared in relation to telemetrically controlled brain temperature. The tolerance to an injurious 3 min test of global forebrain ischemia in Mongolian gerbils was induced 48 h earlier by 2 min preconditioning ischemia. Normothermic preconditioning was virtually harmless, and greatly reduced neurodegeneration evoked by test ischemia. In hyperthermic animals it was injurious and failed to induce tolerance. Memantine (5 mg/kg) and (+)MK-801 (3 mg/kg) injected i.p. 1 h before preconditioning did not inhibit ischemic tolerance in the normothermic gerbils, while in hyperthermic animals treated with (+)MK-801 ischemic tolerance was partially restored. Subchronic 3 day infusion of memantine (30 mg/kg/day) significantly decreased neurodegeneration, and preconditioning in the normothermic gerbils further reduced neuronal damage. Hyperthermia exacerbated preconditioning ischemia and in this way reduced expression of tolerance, while (+)MK-801 partially reversed this effect. Our results do not confirm previous reports on the role of NMDA receptors in the induction of ischemic tolerance in gerbils.
Duszczyk
M
M
Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Gadamski
R
R
Ziembowicz
A
A
Danysz
W
W
Lazarewicz
J W
JW
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000503:physiopathology*; D002339:Carotid Arteries / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019194:Ischemic Preconditioning; D008297:Male; D008559:Memantine / Q000494:pharmacology; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013686:Telemetry
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D008559:Memantine