| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
The brain is exquisitely vulnerable to ischemia, and there are few valid therapies for brain infarction after ischemia. Since inflammation is a crucial factor in the development of ischemia-induced brain injury, prevention of inflammation after reperfusion may be a principal therapy for brain infarction after the onset of ischemia. Histamine is induced after inflammation, and the induced histamine has been shown to suppress inflammation through histamine H2 receptors. In the present study, we investigated prevention of ischemia-induced brain injury by an increase in the brain concentration of histamine after ischemia. Focal cerebral ischemia for 2 h by occlusion of the right middle cerebral artery provoked severe brain infarction in the rat brain after 24 h. Systemic administration of histidine, a precursor of histamine, dose-dependently alleviated brain infarction. Intracerebroventricular administration of ranitidine, an H2 antagonist, completely abolished the alleviation caused by histidine. Simultaneous administration of thioperamide, an H3 antagonist, or metoprine, an inhibitor of histamine-N-methyltransferase, with histidine further reduced the infarct size. In a gerbil model of transient forebrain ischemia for 4 min by occlusion of the bilateral common carotid arteries provoked severe neuronal damage in the hippocampal neurons after 7 days. Post ischemic administration of histidine alleviated neuronal death more effectively than by postischemic mild hypothermia under pentobarbital anesthesia. Furthermore, beneficial effects of histidine were enhanced by thioperamide and shown even 60 days. Histidine, histamine H3 antagonists, and inhibitors of histamine-N-methyltransferase may be new therapeutic agents against brain infarction.
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