Naoi M, Maruyama W
Department of Brain Sciences, Institute of Applied Biochemistry, Mitake, Gifu, Japan.
Mech Ageing Dev. 1999 Nov;111(2-3):175-88. doi: 10.1016/s0047-6374(99)00064-0.
Dopamine neurons in the substantia nigra of human brain are selectively vulnerable and the number decline by aging at 5-10% per decade. Enzymatic and non-enzymatic oxidation of dopamine generates reactive oxygen species, which induces apoptotic cell death in dopamine neurons. Parkinson's disease (PD) is also caused by selective cell death of dopamine neurons in this brain region. The pathogenesis of Parkinson's disease remains to be an enigma, but it was found that an endogenous MPTP-like neurotoxin, 1(R), 2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol, NM(R)Sal], may be one of the pathogenic agents of PD. NM(R)Sal increases in cerebrospinal fluid from untreated parkinsonian patients, and two enzymes, a (R)salsolinol synthase and a neutral N-methyltransferase, synthesize this neurotoxin in the nigro-striatum. The activity of a neutral N-methyltransferase is significantly higher in lymphocytes from parkinsonian patients than in control. The mechanism of cell death by this toxin was proved to be by the induction of apoptosis, by use of dopaminergic SH-SY5Y cells. The apoptosis was suppressed by anti-oxidants, suggesting that the generation of reactive oxygen species may initiate cellular death process. These results indicate that in aging and PD oxidative stress induces degeneration of dopamine neurons, and the antioxidant therapy may delay the decline of dopamine neurons in the brain.
人类大脑黑质中的多巴胺能神经元具有选择性易损性，其数量每十年会以5% - 10%的速度随衰老而减少。多巴胺的酶促氧化和非酶促氧化会产生活性氧，从而诱导多巴胺能神经元发生凋亡性细胞死亡。帕金森病（PD）也是由该脑区多巴胺能神经元的选择性细胞死亡所引起。帕金森病的发病机制仍是一个谜，但已发现一种内源性MPTP样神经毒素，1（R），2（N）-二甲基-6,7-二羟基-1,2,3,4-四氢异喹啉[N-甲基（R）-萨索林醇，NM（R）Sal]，可能是帕金森病的致病因子之一。未经治疗的帕金森病患者脑脊液中NM（R）Sal含量升高，并且两种酶，即（R）-萨索林醇合酶和一种中性N-甲基转移酶，在黑质纹状体中合成这种神经毒素。帕金森病患者淋巴细胞中中性N-甲基转移酶的活性显著高于对照组。利用多巴胺能SH-SY5Y细胞，已证明该毒素导致细胞死亡的机制是诱导细胞凋亡。抗氧化剂可抑制细胞凋亡，这表明活性氧的产生可能启动细胞死亡过程。这些结果表明，在衰老和帕金森病中，氧化应激会诱导多巴胺能神经元变性，抗氧化治疗可能会延缓大脑中多巴胺能神经元的减少。
