TETRAHYDROISOQUINOLINES AND PARKINSON'S DISEASE

描述(由申请人提供)：双胞胎和流行病学研究表明，环境因素有助于特发性帕金森病的发展。帕金森氏症可能的非遗传风险因素包括井水使用、农村生活以及接触杀虫剂和除草剂。杀虫剂鱼藤酮可以抑制呼吸链的复合体I，并导致大鼠帕金森氏症。在“合成海洛因”中掺入MPTP与年轻人患上帕金森症的更显著的联系，激发了人们对其他可能导致黑质细胞死亡的外源性毒素的兴趣。四氢异喹啉衍生物是内源性和外源性神经毒素，在各种模型系统中已被证明能引起多巴胺能功能障碍和细胞死亡。已在食品中检测到一些四氢异喹啉衍生物，其中一些化合物可以穿过血脑屏障。四氢异喹啉衍生物也可以通过儿茶酚胺与醛的缩合在内源形成。关于四氢异喹啉衍生物在神经退行性变中的作用，关键的问题仍然没有回答。该项目将检验三个相互关联的假设：(1)四氢异喹啉衍生物在正常衰老的情况下积聚在中枢神经系统神经元，尤其是多巴胺能神经元中；(2)四氢异喹啉衍生物可导致啮齿类动物多巴胺能神经元的细胞凋亡；(3)四氢异喹啉及其一个或多个衍生物存在于各种水果和蔬菜中。四氢异喹啉衍生物可通过多种内源性和/或外源性途径在神经元中蓄积。正常的代谢途径可能会在不经意间将多巴胺等化合物转化为有毒的副产物，如1，2-二甲基-6，7-二羟基异喹啉离子。神经元或神经胶质酶也可以将食物中存在的外源化学物质，如四氢异喹啉转化为神经毒素，N-甲基异喹啉离子。进化可能没有为神经元提供机制来防止这些正常新陈代谢的副产物积累，结果是，易感神经元群体可能在老年人中缓慢经历凋亡性死亡。

DESCRIPTION (provided by applicant): Twin and epidemiological studies suggest that environmental factors contribute to the development of idiopathic Parkinson's disease. Possible non-genetic risk factors for Parkinson's disease include well water use, rural living, and exposure to pesticides and herbicides. The insecticide rotenone can inhibit complex I of the respiratory chain and cause Parkinsonism in rats. The more striking association of the "synthetic heroin" adulterant MPTP with the development of Parkinsonism in young adults stimulated interest in other possible exogenous toxins that may cause cell death in the substantia nigra. Tetrahydroisoquinoline derivatives are endogenous and exogenous neurotoxins that have been shown to produce dopaminergic dysfunction and cell death in various model systems. Some tetrahydroisoquinoline derivatives have been detected in foods and some of these compounds can cross the blood-brain barrier. Tetrahydroisoquinoline derivatives can also be formed endogenously by condensation of catecholamines with aldehydes. Critical unanswered questions remain regarding the role of tetrahydroisoquinoline derivatives in neurodegeneration. This project will test three interrelated hypotheses: (1) tetrahydroisoquinoline derivatives accumulate in central nervous system neurons, particularly dopaminergic, with normal aging, (2) tetrahydroisoquinoline derivatives can cause apoptotic cell death of dopaminergic neurons in rodents, and (3) tetrahydroisoquinoline and one or more of its derivatives are present in a variety of fruits and vegetables. Tetrahydroisoquinoline derivatives may accumulate in neurons through various combinations of endogenous and/or exogenous pathways. Normal metabolic pathways may "inadvertently" convert compounds such as dopamine to toxic by-products such as 1,2-dimethyl-6,7-dihydroxyisoquinolium ion. Neuronal or glial enzymes may also convert exogenous chemicals present in foods such as tetrahydroisoquinoline to the neurotoxin, N-methylisoquinolinium ion. Evolution may have not provided neurons with mechanisms to prevent accumulation of these by-products of normal metabolism and, as a consequence, susceptible neuronal populations may slowly undergo apoptotic death in the elderly.