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Analysis of the mechanisims of protection of midbrain dopaminergic neurons by the innervation target with the usage of slice culture preparation

切片培养制剂分析神经支配靶点保护中脑多巴胺能神经元的机制

基本信息

批准号：
12672110
负责人：
KATSUKI Hiroshi
金额：
$ 2.3万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672110/
关键词：
Nitric oxide Glutamate Neuronal death Reactive oxygen species Dopamine neuron Parkinson's disease

项目摘要

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 … More 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

本研究旨在利用脑切片培养制剂揭示有助于保护和维持中脑黑质多巴胺能神经元功能的因素。 1.当中脑切片培养物中的多巴胺能神经元与纹状体切片共培养时，它们获得了对 NMDA 和 NO 供体的细胞毒性的抵抗力。在单一中脑培养物中，NMDA 诱导的多巴胺能神经元损失可被 NO 合酶抑制剂抑制。单一中脑培养物中多巴胺能神经元的 ONOO 产生水平高于中脑-纹状体共培养物。此外，与单独培养的中脑组织相比，与纹状体共培养的中脑组织表现出超氧化物歧化酶（SOD）活性水平升高以及铜、锌-SOD蛋白水平升高。因此，纹状体组织（中脑多巴胺能神经元的神经支配目标）的相互作用会导致中脑内 SOD 的增加，这可能导致多巴胺能神经元对兴奋性毒性的抵抗力增加。 2.发现在长期存在L型电压依赖性Ca^2+通道或电压依赖性Na^+通道阻断剂的情况下培养中脑切片会引起多巴胺能神经元数量的急剧减少。这些作用被引起细胞内环AMP水平升高的同时治疗所减弱，这表明自发的神经元活动和由此产生的Ca 2+ 流入神经元细胞质有助于通过涉及环AMP产生的机制维持多巴胺能神经元。 3. 一系列具有 s 受体配体特性的化合物被发现通过调节 NMDA 受体的功能，对多巴胺能神经元免受兴奋性毒性损伤提供显着的保护。这些结果揭示了中脑多巴胺能神经元内源性保护系统的几个方面，这可能有助于建立预防和治疗帕金森病的新策略。较少的