Charlton C G, Crowell B
Division of Basic Pharmaceutical Sciences, Florida A and M University, Tallahassee 32307, USA.
Mol Chem Neuropathol. 1995 Dec;26(3):269-84. doi: 10.1007/BF02815143.
The major symptoms of Parkinson disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by the degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal DA terminals. Norepinephrine (NE) and serotonin (5-HT) levels in the neostriatum and tyrosine hydroxylase and melanin pigments in the substantia nigra are also decreased, and brain cholinergic activity is increased. The cause of PD is unknown, but PD is an age-related disorder, suggesting that changes that occur during the aging process may help to precipitate PD. Methylation increases in aging animals. Increased methylation can deplete DA, NE, and 5-HT; increase acetylcholine; and cause hypokinesia and tremors. These effects are similar to changes seen in PD, and interestingly also, they are similar to some of the changes that are associated with the aging process. It is suggested, therefore, that increased methylation may be an inducing factor in parkinsonism. Accordingly, the effects of an increase in methylation in the brain of rats were studied. S-adenosylmethionine (AdoMet), the limiting factor in the methylation process, was injected into the lateral ventricle of rats. Specific behavioral changes that resemble changes seen in PD were investigated. The results showed that AdoMet caused tremors, rigidity, hypokinesia, and depleted DA. The hypokinetic effects of a single dose of AdoMet lasted for about 90 min. AdoMet has a dose-dependent hypokinetic effect. A dose of 9.4 nmol reduced movement time (MT) by 68.9% and increased rest time (RT) by 20.7%, and a dose of 400 nmol reduced MT by 92.4% and increased RT by 27.6%. The normethyl analog of AdoMet, S-adenosylhomocysteine, did not cause hypokinesia or tremors, but it blocked the AdoMet-induced motor effects. L-dopa, the precursor of DA, also blocked the AdoMet-induced motor effects. These data suggest that the methyl group of AdoMet as well as DA depletion are involved in the AdoMet-induced motor effects. A dose of 0.65 mumol of AdoMet depleted DA in the ipsilateral caudate nucleus (CN) or neostriatum by 50.1%, and DA in the contralateral CN was reduced by 9.3%. Double the dose of AdoMet did not increase the depletion of DA on the ipsilateral CN, but DA in the contralateral CN was decreased by 26.3%. Taken together, the results suggest that increased methylation may contribute to the symptoms of PD.
帕金森病（PD）的主要症状包括震颤、运动迟缓、僵硬和姿势异常，这些症状是由黑质（SN）中多巴胺（DA）神经元的退化以及新纹状体DA终末中DA的缺乏引起的。新纹状体中的去甲肾上腺素（NE）和5-羟色胺（5-HT）水平以及黑质中的酪氨酸羟化酶和黑色素也会降低，而脑胆碱能活性会增加。PD的病因尚不清楚，但PD是一种与年龄相关的疾病，这表明衰老过程中发生的变化可能有助于引发PD。衰老动物的甲基化会增加。甲基化增加会消耗DA、NE和5-HT；增加乙酰胆碱；并导致运动迟缓与震颤。这些影响与PD中观察到的变化相似，有趣的是，它们也与衰老过程相关的一些变化相似。因此，有人提出甲基化增加可能是帕金森症的诱发因素。据此，研究了大鼠脑中甲基化增加的影响。将甲基化过程中的限制因子S-腺苷甲硫氨酸（AdoMet）注入大鼠侧脑室。研究了类似于PD中所见变化的特定行为变化。结果表明，AdoMet会引起震颤、僵硬、运动迟缓并消耗DA。单剂量AdoMet的运动迟缓作用持续约90分钟。AdoMet具有剂量依赖性的运动迟缓作用。9.4 nmol的剂量使运动时间（MT）减少了68.9%，休息时间（RT）增加了20.7%，400 nmol的剂量使MT减少了92.4%，RT增加了27.6%。AdoMet的去甲基类似物S-腺苷同型半胱氨酸不会引起运动迟缓或震颤，但它会阻断AdoMet诱导的运动效应。DA的前体左旋多巴（L-dopa）也会阻断AdoMet诱导的运动效应。这些数据表明，AdoMet的甲基基团以及DA的消耗都参与了AdoMet诱导的运动效应。0.65 μmol的AdoMet剂量使同侧尾状核（CN）或新纹状体中的DA消耗了50.1%，对侧CN中的DA减少了9.3%。AdoMet剂量加倍并没有增加同侧CN中DA的消耗，但对侧CN中的DA减少了26.3%。综上所述，结果表明甲基化增加可能导致PD的症状。
