| Budget Amount *help |
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥5,800,000 (Direct Cost: ¥5,800,000)
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| Research Abstract |
Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon a brain insult, ATP is released from damaged cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor nectosis factor (TNF). The release of TNF appears to be dependent on the P2X_7 receptor. The inhibitors, U0126, SP600125 and SB203580, which target MEK, JNK and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38, but not ERK, could be inhibited by brilliant blue G, a P2X_7 receptor blocker, and by genistein and PP2, general and src-family specific tyrosine kinase inhibitors, respectively. The treatment of the microglia in neurone-microglia co-cultures with the P2X_7 agonist BzATP led to
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significant neuroprotective effects. On the other hand, LPS caused massive TNF release, but did not exert any protective effects on glutamate neurotoxity. In rat primary cultured microglia, α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed, and the activation of this receptor by nicotine enhanced P2X_7 receptor-mediated TNF release, whilst suppressing LPS-induced TNF release. This response was independent of extracellular Ca^<2+> and blocked by U73122 and xestospongin C, inhibitors of phospholipase C and IP_3 receptor, respectively. In addition, nicotine-induced currents were not detected, suggesting that α7 nAChR may not function as conventional ion channels. This novel α7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function. Furthermore, intracerebroventricular injection of microglia protected neurodegeneration in brain ischemic model rats. Less
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