| Co-Investigator(Kenkyū-buntansha) |
ABE Hiroshi Kanazawa Medical University, Medical, Lecturer, 医学部, 講師 (30175913)
MATSUDA Tomio Kanazawa Medical University, Medical, Lecturer, 医学部, 講師 (70181732)
UEDA Yoshimichi Kanazawa Medical University, Medical, Assistant Professor, 医学部, 助教授 (50271375)
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| Budget Amount *help |
¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
This study examined the molecular mechanism of delayed neuronal death using a mongolian gerbil, model for transient isohemia, and focused particularly on the induction of apoptosis by nitric oxide (NO). In the hippocampal CAl pyramidal neurons, inducible NO synthase (iNOS) was induced at the message level at 6 hours, and at the protein level at 24 hours following transient ischemia. Nitrotyrosine formation was detected in the hippocampal CAl layer, indicating that peroxynitrite (0N00), a cytotoxic oxidant, was produced from N0 by the interaction with superoxide (0_2). Aminoguanidine 320 mg/kg, injected intra-peritoneally, suppressed fragmentation of DNA, as well as production of ONOO in the hippocampal CAl pyramidal neurons. Intraischemic mild hypothermia (34ﾟC) inhibited both the decrease of bcl-2 and induction of iNOS in the hippocampal CAl pyramidal neurons. It also ameliorated delayed neuronal death in the same region. Furthermore, activation of NF-_KB, one of the important inducers of the iNOS gene, was detected in the hippocampal CAl layer at 20 to 30 min after transient ischemia. These results clearly showed that iNOS expressed in the hippocampal CAl pyramidal neurons soon after transient ischemia and reperfusion was involved upstream of the apoptosis-induction mechanism, indicating that N0 and 0N00 produced by iNOS may have various functions. Transcription of the iNOS gene in the pyramidal neurons seems to be up-regulated by NF-_KB, which is activated by calcium-signaling due to excitatory amino acid neurotoxicity after transient ischemia and reperfusion. In addition, FasL was expressed in the hippocampal CAl pyramidal neurons after transient ischemia. The expression of FasL may also be involved upstream of the apoptosis-induction mechanism, or it may play a significant role in immune privilege for the central nervous system.
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