Charlton C G, Crowell B
Department of Physiology, Meharry Medical College, Nashville, TN 37208.
Pharmacol Biochem Behav. 1992 Oct;43(2):423-31. doi: 10.1016/0091-3057(92)90172-c.
The major symptoms of Parkinson's disease (PD) are due to degeneration of the nigrostriatal pathway and depletion of dopamine (DA). Tyrosine hydroxylase (TH), norepinephrine (NE), serotonin (5-HT), and melanin pigments are also decreased and acetylcholinergic activity increased. Biochemically, increased methylation can cause the depletion of DA, NE, 5-HT, and melanin pigments and also an increase of acetylcholine; thus, increased methylation can present a biochemical picture that resembles the biochemical changes that occur in PD. During the therapy of PD with L-dopa, it is well known that L-dopa reacts avidly with S-adenosyl-L-methionine (SAM), the biologic methyl donor, to produce 3-O-methyl-dopa. Correspondingly, L-dopa has been shown to deplete the concentration of SAM, and SAM has been found to induce PD-like motor impairments in rodents; therefore, an excess of SAM-dependent methylation may be associated with Parkinsonism. To further study the effects of methylation, SAM was injected into the lateral ventricle of rats. SAM caused tremors, rigidity, abnormal posture, and dose-related hypokinesia. Doses of 9.38, 50, and 400 nM/rat caused 61.9, 73.4, and 94.8% reduction, respectively, of motor activity. A 200-mg/kg IP dose of L-dopa, given before 50 nM SAM, blocked the SAM-induced hypokinesia. SAM also caused a decrease in TH immunoreactivity, apparent degeneration of TH-containing fibers, loss of neurons, and the accumulation of phagocytic cells in the substantia nigra. These results showed that excess SAM in the brain, probably due to its ability to increase methylation, can induce symptoms that resemble some of the changes that occur in PD.
帕金森病（PD）的主要症状是由于黑质纹状体通路变性和多巴胺（DA）耗竭所致。酪氨酸羟化酶（TH）、去甲肾上腺素（NE）、5-羟色胺（5-HT）和黑色素也减少，而乙酰胆碱能活性增加。从生化角度来看，甲基化增加可导致DA、NE、5-HT和黑色素耗竭，同时乙酰胆碱增加；因此，甲基化增加可呈现出与PD中发生的生化变化相似的生化图景。在用左旋多巴治疗PD期间，众所周知，左旋多巴与生物甲基供体S-腺苷-L-甲硫氨酸（SAM）发生剧烈反应，生成3-O-甲基多巴。相应地，已证明左旋多巴会消耗SAM的浓度，并且发现SAM会在啮齿动物中诱发类似PD的运动障碍；因此，过量的SAM依赖性甲基化可能与帕金森症有关。为了进一步研究甲基化的影响，将SAM注入大鼠侧脑室。SAM引起震颤、僵硬、异常姿势以及与剂量相关的运动迟缓。剂量为9.38、50和400 nM/大鼠时，分别导致运动活性降低61.9%、73.4%和94.8%。在给予50 nM SAM之前给予200 mg/kg腹腔注射剂量的左旋多巴，可阻断SAM诱导的运动迟缓。SAM还导致TH免疫反应性降低、含TH纤维明显变性、神经元丢失以及黑质中吞噬细胞积聚。这些结果表明，大脑中过量的SAM可能由于其增加甲基化的能力，可诱发类似于PD中出现的一些变化的症状。
