| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
This study was aimed to reveal factors contributing to the protection and the maintenance of functions of nigral dopaminergic neurons in the midbrain, using brain slice culture preparations. 1. Dopaminergic neurons in midbrain slice cultures acquired resistance to the cytotoxicity of NMDA and NO donors, when they were co-cultured with the striatal slices. NMDA-induced loss of dopaminergic neurons in single midbrain cultures was suppressed by an NO synthase inhibitor. The levels of ONOO production in dopaminergic neurons were higher in single midbrain cultures than in midbrain-striatum co-cultures. In addition, midbrain tissues co-cultured with the striatum exhibited an increased level of superoxide dismutase (SOD) activity as well as an increased level of Cu,Zn-SOD proteins, compared to midbrain tissues cultured alone. Therefore, interactions of the striatal tissue, an innervation target of the midbrain dopaminergic neurons, result in an increase in SOD within the midbrain, which may c
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ontribute to the increased resistance of dopaminergic neurons to excitotoxicity. 2. Cultivation of midbrain slices in the chronic presence of blockers of L-type voltage-dependent Ca^<2+> channels or voltage-dependent Na^+ channels was found to cause a dramatic decrease in the number of dopaminergic neurons. These effects were attenuated by concurrent treatments that caused elevation of intracellular levels of cyclic AMP, suggesting that spontaneous neuronal activity and resultant Ca^<2+> influx into neuronal cytoplasm contribute to the maintenance of dopaminergic neurons through the mechanisms involving cyclic AMP production. 3. A series of compounds with properties of s receptor ligands were found to afford remarkable protection of dopaminergic neurons against excitotoxic insults, by modulating the functions of NMDA receptors. These results revealed several aspects of endogenous protective systems for midbrain dopaminergic neurons, which may contribute to the establishment of novel strategies for prevention and treatment of Parkinson's disease. Less
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