| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Hippocampal neuronal death after ischemia is generally explained by an excessive release of excitatory amino acid. Several lines of evidence, however, indicate that interleukin (IL)-1 is also released in the brain under ischemic conditions. In this research project, therefore, I examined whether IL-1 is involved in the process of excitotoxic neuronal death. Cultured mouse hippocampal slices were exposed to 50μM of N-methyl-D-aspartate (NMDA) for 15 min and neuronal death was evaluated 48 hr later. Application of IL-1 receptor antagonist (IL-1RA) immediately following the NMDA insult inhibited the neuronal death concentration-dependently. A time-window study revealed that the neuroprotective action of IL-RA was exerted during the initial 24 hr after the NMDA exposure. Cotreatment with IL-1β (500 ng/ml) reversed the protective effect of IL-1RA, but IL-1β per se did not affect the neuronal survival. Furthermore, the NMDA-induced neuronal death was depressed in slices prepared from IL-1α/β double-deficient mice compared with those from wild type mouse. To clarify the source of IL-1, I next examined the IL-1 concentration in the culture media of neuronal and microglial cells with a bioassay system. Exposure to 500 μM of NMDA for 15 min increased the extracellular concentration of IL-1 in microglial culture, but not in hippocampal neuronal culture. These results indicate that IL-1 is released, at least partly, from microglia and potentiates the NMDA toxicity.
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