title: Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia.
abstract: 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.
authors.affiliation: Department of Pharmacology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. kimori@med.hokudai.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.forename: H
authors.initials: H
authors.lastname: Togashi
authors.forename: K I
authors.initials: KI
authors.lastname: Ueno
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Yoshioka
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine