Post-ischemic administration [correction of administeration] but not pre-ischemic administration [correction of administeration] of NG-nitro-L-arginine prevents spatial memory impairments and apoptosis by an inhibition of a delayed increase in NOx- in the hippocampus following repeated cerebral ischemia.
In the present study, we investigated the effects of N(G)-nitro-L-arginine (L-NAME), an inhibitor of nitric oxide synthase, on repeated cerebral ischemia-induced impairment of spatial memory of the 8-arm radial maze in rats. Repeated ischemia (10 min ischemia x 2 times with 1 h interval) impaired the spatial memory in the 8-arm radial maze test and produced apoptosis in the hippocampus 7 days after final occlusion, and gradually increased the NO(x)(-) levels approximately 30-180 min after the second reperfusion. Post-ischemic administration of L-NAME at a dose of 50 mg/kg, i.p. 30 min following the second occlusion, significantly attenuated the repeated ischemia-induced impairment of spatial memory in the 8-arm radial maze test and suppressed apoptosis in the hippocampus, and also significantly suppressed a delayed increase in the NO(x)(-) levels induced by repeated ischemia. However, pre-ischemic administration of L-NAME at a dose of 50 mg/kg, i.p. 30 min before the first occlusion, caused about 90% mortality (the mortality rate of vehicle-treated group was 10%). These results suggest that the delayed generation of NO(x)(-) may cause spatial memory impairment and induction of apoptosis in the hippocampus in rats subjected to repeated ischemia.
Mishima
K
K
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Pu
F
F
Kaneko
T
T
Egashira
N
N
Iwasaki
K
K
Fujiwara
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000523:psychology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase