Charlton C G, Mack J
Department of Pharmacology, Meharry Medical College, Nashville, TN 37208.
Mol Neurobiol. 1994 Aug-Dec;9(1-3):149-61. doi: 10.1007/BF02816115.
The major symptoms of Parkinson's disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal dopaminergic terminals. Norepinephrine, serotonin, and melanin pigments are also decreased and cholinergic activity is increased. The cause of PD is unknown. Increased methylation reactions may play a role in the etiology of PD, because it has been observed recently that the CNS administration of S-adenosyl-L-methionine (SAM), the methyl donor, caused tremors, hypokinesia, and rigidity; symptoms that resemble those that occur in PD. Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly, L-DOPA, the most effective drug used to treat PD, reacts avidly with SAM. So methylation may be important in PD; an idea that is of particular interest because methylation reactions increase in aging, the symptoms of PD are strikingly similar to the neurological and functional changes seen in advanced aging, and PD is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration. To know this, the effects of an increase in methylation in the brain were studied by injecting SAM into the lateral ventricle of rats. The injection of SAM caused neuronal degeneration, noted by a loss of neurons, gliosis, and increased silver reactive fibers in the SN. The degeneration was accompanied with a decrease in SN tyrosine hydroxylase (TH) immunoreactivity, and degeneration of TH-containing fibers. At the injection site in the lateral ventricle it appears that SAM caused a weakening or dissolution of the intercellular substances; observed as a disruption of the ependymal cell layer and the adjacent caudate tissues. SAM may also cause brain atrophy; evidenced by the dilation of the cerebral ventricle. Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.
帕金森病（PD）的主要症状为震颤、运动迟缓、僵硬及姿势异常，这些症状由黑质（SN）中多巴胺（DA）神经元变性以及新纹状体多巴胺能终末处DA缺乏所致。去甲肾上腺素、5-羟色胺及黑色素也会减少，胆碱能活性则会增强。PD的病因尚不清楚。甲基化反应增加可能在PD的病因中起作用，因为最近观察到，向中枢神经系统给药甲基供体S-腺苷-L-甲硫氨酸（SAM）会引发震颤、运动迟缓及僵硬，这些症状与PD中出现的症状相似。此外，PD中出现的许多生化变化类似于如果大脑中依赖SAM的甲基化反应增加可能发生的变化，有趣的是，用于治疗PD的最有效药物左旋多巴（L-DOPA）与SAM反应剧烈。因此，甲基化可能在PD中起重要作用；这一观点特别值得关注，因为甲基化反应在衰老过程中会增加，PD的症状与衰老晚期出现的神经和功能变化极为相似，且PD与年龄相关。若甲基化在PD中被视为重要因素，那就意味着，除了其生化反应和行为效应外，甲基化增加还应导致特定的神经元变性。为了解这一点，通过向大鼠侧脑室注射SAM来研究大脑中甲基化增加的影响。注射SAM导致神经元变性，表现为黑质中神经元丢失、胶质细胞增生以及银反应性纤维增加。这种变性伴随着黑质酪氨酸羟化酶（TH）免疫反应性降低以及含TH纤维的变性。在侧脑室的注射部位，SAM似乎导致细胞间物质减弱或溶解，表现为室管膜细胞层和相邻尾状组织的破坏。SAM还可能导致脑萎缩，表现为脑室扩张。在大鼠模型中观察到的大多数SAM诱导的解剖学变化与PD中发生的变化相似，这进一步支持了依赖SAM的甲基化增加在PD中的作用。
