| Budget Amount *help |
¥3,880,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
1. NMDA receptor activation and vasopressin fragment
In recent years, it is reported that activation of cyclooxygenase (COX) increased NMDA receptors activity. Therefore, we investigated relationships between COX and learning and/or memory. To examine the participation of COX-3 on memory formation, water maze performance was studied in mice treated with acetaminophen (AAP), phenacetin (PHE) or other COX inhibitors. Mice received intraperitoneal injections of drugs immediately after each training session. The administration of AAP[302.3 mg/kg (over the IC_<50> for COX-2) ]or PHE[179.2 mg/kg (IC (50) for COX-2) ]and of a non-specific (indomethacin : 20 mg/kg) or specific COX-2 (NS-398 : 20 mg/kg) inhibitor impaired the performance in hidden platform (HP) not visible platform (VP) tasks, whereas the low-dose (15.1 mg/kg) AAP facilitated performance in HP and VP tasks. The facilitation of performance by the low-dose AAP was reversed by co-administration with a 5-HT_1/2 receptor antagonist (
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methysergide : 0.47 mg/kg). The middle-dose[69.5 mg/kg (IC_<50> for COX-3) ]AAP, the low-dose PHE[17.9 mg/kg (IC_<50> for COX-3) ],and a specific COX-1 inhibitor (piroxicam : 10-20 mg/kg) did not influence performance in either task. These results suggest that administration of selective COX-3 inhibitors modulated cognitive function. The memory impairment and the facilitation of performance could involve endogenous COX-2 and serotonergic neuronal activity, respectively, but not COX-3.
2. COX and mnemonic effect induced by vasopressin fragment
We investigated the effect of administration of inhibitors of each of the arachidonic acid metabolism pathways and co-administration of NC-1900, a fragment analog of arginine vasopressin, with these inhibitors could influence latency on the step-through passive avoidance task. Intracerebroventricular (i.c.v.) administration of nordihydroguaiaretic acid (NDGA) (10 μg), a phospholipase A_2 (PLA_2) and lipoxygenase (LOX) inhibitor, and of arachidonyl trifluoromethyl ketone (ATK) (10μg), a specific PLA2 inhibitor caused reductions in latency on the retention trial (Ret.). The i.c.v. administration of either of baicalein, a 12-LOX inhibitor, or AA-861, a 5-LOX inhibitor, did not influence the latency. I.p. administration of indomethacin (IND: 20 mg/kg), a non-specific COX inhibitor, or NS-398 (10 mg/kg), a specific COX-2 inhibitor, impaired performance on Ret., while piroxicam, a specific COX-1 inhibitor, did not. S.c. administration of NC-1900 (0.1 ng/kg) ameliorated the reduction of latency caused by NDGA, ATK, IND, or NS-398. These results suggested that the ameliorating effect of NC-1900, in part, is due to mimicking of the effects of metabolites of the COX-2 pathway.
3. Conclusion
Above-mentioned, it is suggested that cyclooxygenase pathway participate in activation of NMDA receptor, and that the activation of NMDA receptor may induce a mnemonic effect on learning and memory. Less
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