Cox-2 deficient mice are resistant to MPTP neurotoxicity

Cox-2缺陷小鼠对MPTP神经毒性有抵抗力

• 批准号: 6894804
• 负责人: Guoying Bing
• 金额: $ 27.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894804
• 关键词: Parkinson' s disease; RNase protection assay; apoptosis; automated data processing; behavior test; biological signal transduction; cytokine; dopamine; enzyme activity; free radical oxygen; functional ability; high performance liquid chromatography; inflammation; laboratory mouse; methylphenyltetrahydropyridine; microglia; mitochondria; neural degeneration; neurons; neuropharmacology; neurotoxicology; oxidative stress; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; substantia nigra; terminal nick end labeling

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc). Loss of SNpc dopaminergic neurons results in the depletion of striatal dopamine levels and produces symptoms such as tremor, muscle rigidity, and bradykinesia. The etiology of PD is unknown, but chronic inflammatory processes, microglial activation, and oxidative stress are thought to play prominent roles in the degeneration of dopaminergic neurons in the SNpc. Microglia are thought to contribute to neurodegeneration by releasing cytotoxic agents such as pro-inflammatory cytokines and reactive oxygen species that increase inflammation and oxidative stress. N-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) is a neurotoxin found to mimic many of the features of PD in animal models, including loss of dopaminergic neurons in SNpc and activation of microglia. Recent observations indicate that cyclooxygenase-2 (COX-2) deficiency in mice reduces the susceptibility of SNpc dopaminergic neurons to MPTP toxicity and diminishes MPTP-induced microglial activation. The purpose of this study is to test the hypothesis that COX-2-regulated inflammatory processes exacerbate MPTP neurotoxicity by activating microglia and increasing oxidative stress that contributes to the degeneration of dopaminergic neurons in the SNpc. To test this hypothesis, mice deficient in the COX-2 gene will be treated with MPTP to determine the role of COX-2 in MPTP-induced neurodegeneration. Furthermore, wild-type mice will be administered exogenous COX-2 inhibitors prior to MPTP treatment to evaluate the protective effects of COX-2 inhibitors against MPTP neurotoxicity. Following these experiments, dopaminergic neuron survival, microglial activation, striatal dopamine levels, and functional recovery will be assessed. In addition, protein modification, generation of reactive oxygen species, expression of inflammatory cytokines and apoptosis-related genes, and activation of specific signaling molecules will be evaluated to determine the molecular mechanisms by which COX-2 exacerbates MPTP neurotoxicity. The goals of this study are to elucidate the changes in inflammatory processing affected by COX-2 deficiency, to explore the etiology and molecular mechanisms underlying Parkinsonian symptoms in the experimental MPTP model, and to develop novel therapeutic treatments for PD and other neurodegenerative diseases.

描述（由申请人提供）：帕金森氏病（PD）是一种运动障碍，其特征是在黑质尼格拉（Nigra）pars compacta（SNPC）中逐渐丧失多巴胺神经元。 SNPC多巴胺能神经元的丧失会导致纹状体多巴胺水平的耗竭，并产生障碍，例如震颤，肌肉僵硬和胸肌。 PD的病因尚不清楚，但是慢性炎症过程，小胶质细胞激活和氧化应激被认为在SNPC中多巴胺能神经元的退化中起着突出的作用。据认为，小胶质细胞通过释放细胞毒性剂（例如促炎性细胞因子）和增加炎症和氧化应激的活性氧来促进神经变性。 N-甲基-4-苯基-1,2,3,6， - 四氢吡啶（MPTP）是一种神经毒素，可以模仿动物模型中PD的许多特征，包括SNPC中多巴胺能神经元的丧失和Microglia激活。最近的观察结果表明，小鼠的环氧合酶-2（COX-2）缺乏降低了SNPC多巴胺能神经元对MPTP毒性的敏感性并减少MPTP诱导的小胶质细胞激活。这项研究的目的是检验以下假设：COX-2调节的炎症过程通过激活小胶质细胞和增加氧化应激加剧了MPTP神经毒性，这有助于SNPC中多巴胺能神经元的退化。为了检验该假设，将使用MPTP处理缺乏COX-2基因的小鼠，以确定COX-2在MPTP诱导的神经变性中的作用。此外，在MPTP处理之前，将向野生型小鼠施用外源COX-2抑制剂，以评估COX-2抑制剂对MPTP神经毒性的保护作用。在这些实验之后，将评估多巴胺能神经元的存活，小胶质细胞活化，纹状体多巴胺水平和功能恢复。此外，将评估蛋白质修饰，活性氧的产生，炎症细胞因子的表达和与凋亡相关的基因的表达以及特定信号分子的激活，以确定COX-2加剧MPTP神经毒性的分子机制。这项研究的目标是阐明受COX-2缺乏症影响的炎症加工的变化，探索实验MPTP模型中帕金森氏症状的病因和分子机制，并开发针对PD和其他神经退行性疾病的新型治疗方法。