Kurosaki R, Muramatsu Y, Michimata M, Matsubara M, Kato H, Imai Y, Itoyama Y, Araki T
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Sendai, Japan.
Neurol Res. 2002 Oct;24(7):655-62. doi: 10.1179/016164102101200717.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway injury similar to that observed in Parkinson's disease. Many hypotheses have been proposed to explain the mechanisms underlying MPTP neurotoxicity. Previous work showed that the inhibitor of neuronal nitric oxide synthase (nNOS) might produce protection against MPTP-induced dopaminergic toxicity. To exactly test the role of NO in MPTP neurotoxicity, we examined the effect of nNOS inhibitor 7-nitroindazole, in comparison with that of nonselective NOS inhibitor (L-NAME), immunosuppressant (FK-506), monoamine oxidase (MAO) inhibitors (clorgyline and pargyline), N-methyl-D-aspartate receptor antagonist (MK-801) and Ca2+ antagonist (amlodipine). Among seven compounds, 7-nitroindazole produced dose-dependent protection against MPTP-induced depletion of striatal dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in mice. Clorgyline and pargyline also showed a significant effect on MPTP-induced dopamine depletion in the mouse striatum. However, both compounds did not protect against MPTP-induced depletion of striatal DOPAC Our immunohistological study with tyrosine hydroxylase (TH) and microtuble-associated protein 2 (MAP 2) showed that 7-nitroindazole or pargyline can protect against MPTP-induced depletion of TH and MAP 2 immunostained neurons in the substantia nigra. Furthermore, these compounds reduced a marked increase in GFAP-positive astrocytes of the mouse striatum after MPTP treatments. The present study demonstrates that nNOS inhibitor 7-nitroindazole as well as MAO inhibitors clorgyline and pargyline can produce dose-dependent neuroprotection against the dopaminergic neurotoxicity of MPTP. However, nonselective NOS inhibitor L-NAME, immunosuppressant FK-506, NMDA receptor antagonist MK-801 and Ca2+ antagonist amlodipine did not show a beneficial effect on MPTP neurotoxicity.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）会导致黑质纹状体多巴胺能通路损伤，这与帕金森病中观察到的情况类似。人们提出了许多假说来解释MPTP神经毒性的潜在机制。先前的研究表明，神经元型一氧化氮合酶（nNOS）抑制剂可能对MPTP诱导的多巴胺能毒性产生保护作用。为了准确测试一氧化氮在MPTP神经毒性中的作用，我们研究了nNOS抑制剂7-硝基吲唑的效果，并与非选择性一氧化氮合酶抑制剂（L-NAME）、免疫抑制剂（FK-506）、单胺氧化酶（MAO）抑制剂（氯吉兰和帕吉林）、N-甲基-D-天冬氨酸受体拮抗剂（MK-801）和钙离子拮抗剂（氨氯地平）进行了比较。在这七种化合物中，7-硝基吲唑对MPTP诱导的小鼠纹状体多巴胺及其代谢产物3,4-二羟基苯乙酸（DOPAC）耗竭具有剂量依赖性保护作用。氯吉兰和帕吉林对MPTP诱导的小鼠纹状体多巴胺耗竭也有显著作用。然而，这两种化合物均不能保护纹状体免受MPTP诱导的DOPAC耗竭。我们用酪氨酸羟化酶（TH）和微管相关蛋白2（MAP 2）进行的免疫组织学研究表明，7-硝基吲唑或帕吉林可以保护黑质中TH和MAP 2免疫染色神经元免受MPTP诱导的耗竭。此外，这些化合物减少了MPTP处理后小鼠纹状体中GFAP阳性星形胶质细胞的显著增加。本研究表明，nNOS抑制剂7-硝基吲唑以及MAO抑制剂氯吉兰和帕吉林可对MPTP的多巴胺能神经毒性产生剂量依赖性神经保护作用。然而，非选择性一氧化氮合酶抑制剂L-NAME、免疫抑制剂FK-506、NMDA受体拮抗剂MK-801和钙离子拮抗剂氨氯地平对MPTP神经毒性未显示出有益作用。
