Abe K, Taguchi K, Wasai T, Ren J, Utsunomiya I, Shinohara T, Miyatake T, Sano T
Department of Neuroscience, Showa Pharmaceutical University, Higashitamagawagakuen, Machida, Tokyo, Japan.
Brain Res Bull. 2001 Sep 1;56(1):55-60. doi: 10.1016/s0361-9230(01)00603-7.
We carried out behavioral, pathological, and biochemical studies in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) affects the onset of Parkinson's disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. Pretreatment with (R)-1-MeTIQ or its racemate (RS)-1-MeTIQ prevented the TIQ-induced bradykinesia. Pretreatment with a combination of L-DOPA and carbidopa significantly prevented subsequent TIQ-induced bradykinesia. Furthermore, the pathological study demonstrated that either (R)-1-MeTIQ or its racemate protected against TIQ-induced loss of tyrosine hydroxylase-positive cells of the substantia nigra pars compacta. (R)-1-MeTIQ and its racemate also prevented the TIQ-induced reduction in the levels of dopamine and its metabolites in the striatum. Serotonin and its metabolite were not affected by repeated administration of (RS)-1-MeTIQ or its derivatives. On the other hand, (S)-1-MeTIQ induced moderate but significant bradykinesia, whereas (R)-1-MeTIQ did not induce this behavioral abnormality at all. In addition, (S)-enantiomer prevented the onset of TIQ-induced bradykinesia, though to a lesser extent than did either (R)-enantiomer or its racemate. However, (S)-enantiomer did not prevent the loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. We concluded that (R)-1-MeTIQ, and not (S)-enantiomer, plays a crucial role in protection against TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of Parkinson's disease.
我们进行了行为学、病理学和生物化学研究，以确定1-甲基-1,2,3,4-四氢异喹啉（1-MeTIQ）的立体结构是否会影响由1,2,3,4-四氢异喹啉（TIQ）在小鼠中诱导的帕金森病样症状的发作。用（R）-1-MeTIQ或其外消旋体（RS）-1-MeTIQ预处理可预防TIQ诱导的运动迟缓。用左旋多巴和卡比多巴联合预处理可显著预防随后TIQ诱导的运动迟缓。此外，病理学研究表明，（R）-1-MeTIQ或其外消旋体均可防止TIQ诱导的黑质致密部酪氨酸羟化酶阳性细胞丢失。（R）-1-MeTIQ及其外消旋体还可防止TIQ诱导的纹状体中多巴胺及其代谢产物水平降低。血清素及其代谢产物不受（RS）-1-MeTIQ或其衍生物重复给药的影响。另一方面，（S）-1-MeTIQ诱导中度但显著的运动迟缓，而（R）-1-MeTIQ根本不诱导这种行为异常。此外，（S）-对映体可预防TIQ诱导的运动迟缓的发作，尽管程度小于（R）-对映体或其外消旋体。然而，（S）-对映体不能防止黑质致密部酪氨酸羟化酶阳性神经元的丢失。我们得出结论，（R）-1-MeTIQ而非（S）-对映体在预防TIQ诱导的帕金森病中起关键作用，这一事实表明，诸如1-MeTIQ生物合成等对映体生物化学事件可能参与帕金森病的发病机制。
