Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia.
The present study was performed to investigate whether increases in nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) were involved in impairment of learning behavior and hippocampal long-term potentiation (LTP) following transient ischemia. Rats with four-vessel occlusion (4-VO) were used as an ischemic model. One week after permanent occlusion of the vertebral arteries, the common carotid arteries were clamped for 10 min under halothane anesthesia. Aminoguanidine (10 mg/kg i.p.), a relatively selective iNOS inhibitor, or saline was administered 30 min before common carotid arteries occlusion, and every 24-h for 4 days. We investigated whether hippocampal NO production was increased by ischemic insult using microdialysis on days 1, 4 and 7 after 4-VO. On days 1 and 4 after 4-VO, increases in NO production were observed, and this effect was inhibited by aminoguanidine. Four days after 4-VO, rats were subjected to the Y-maze test and contextual fear conditioning. Ischemic insults impaired learning behavior, and aminoguanidine ameliorated the impairment induced by 4-VO. Four days after 4-VO, the changes in the population spike amplitude were recorded as an index of LTP in Schaffer collateral-CA1 (carotid artery 1), the mossy fiber-CA3 and the perforant path-dentate gyrus synapses. LTP was significantly inhibited by 4-VO, except in mossy fiber-CA3 synapses. Pretreatment with aminoguanidine prevented the reduction of LTP in perforant path-dentate gyrus, but not in Schaffer collateral-CA1 synapses. These results suggest that post-ischemic increase in NO production via iNOS impaired the learning behavior. There is an association between behavioral performance and LTP formation in perforant path-dentate gyrus synapses, but neither in Schaffer collateral-CA1 nor in mossy fiber-CA3 synapses.
Mori
K
K
Department of Pharmacology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. kimori@med.hokudai.ac.jp
Togashi
H
H
Ueno
K I
KI
Matsumoto
M
M
Yoshioka
M
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005239:Fear / Q000523:psychology; D006146:Guanidines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D002546:Ischemic Attack, Transient / Q000523:psychology*; D007858:Learning / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine