Balijepalli S, Kenchappa R S, Boyd M R, Ravindranath V
Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore 560 029, India.
Neurochem Int. 2001 Apr;38(5):425-35. doi: 10.1016/s0197-0186(00)00108-x.
Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, alpha-lipoic acid and glutathione isopropyl ester, and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract.
使用“典型”而非“非典型”抗精神病药物与涉及锥体外系（EPT）的严重副作用相关。单剂量的氟哌啶醇导致额叶皮质、纹状体和中脑的复合体I选择性抑制（分别为41%和26%），用硫醇抗氧化剂、α-硫辛酸和谷胱甘肽异丙酯预处理小鼠可消除这种抑制，并且在体外，二硫苏糖醇这种二硫键还原剂可使其逆转。对小鼠长期给予氟哌啶醇会导致额叶皮质、海马体、纹状体和中脑的复合体I丧失，而长期服用氯氮平仅影响海马体和额叶皮质。利培酮导致额叶皮质、海马体和纹状体的复合体I丧失，但不影响发出锥体外系的中脑。在体内，氟哌啶醇对电子传递链成分复合体I的抑制是通过将必需的硫醇基团氧化为二硫键来介导的。此外，抗精神病药物导致锥体外系脑区复合体I的丧失与其已知的产生涉及锥体外系的副作用的倾向相关。
