Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
Pharmacol Rep. 2013;65(5):1204-12. doi: 10.1016/s1734-1140(13)71478-6.
Selegiline, a therapeutic drug for Parkinson's disease (PD), structurally resembles the endogenous parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline (TIQ). In the present study, we evaluated the effects of 3-methyl-TIQ (3-MeTIQ) and 3-methyl-N-propargyl-TIQ (3-Me-N-proTIQ), selegiline mimetic TIQ derivatives, for preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism-like symptoms in mice.
We evaluated the preventative effects of 3-MeTIQ and 3-Me-N-proTIQ on MPTP-induced bradykinesia and depletion of striatal dopamine (DA) and nigral tyrosine hydroxylase (TH)-positive cells.
MPTP-induced bradykinesia was not different when mice were pretreated with 3-MeTIQ, except for the high-dose group. However, pretreatment with 3-Me-N-proTIQ significantly prevented the appearance of this akinesic status. MPTP-induced striatal DA and 3,4-dehydroxyphenylacetic acid reduction were significantly prevented by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ, in a dose-dependent manner. On the other hand, levels of serotonin and its metabolite, 5-hydroxyindole acetic acid, in the striatum were increased following treatment with 3-MeTIQ. In addition, the MPTP-induced decrease in TH-positive cells in the substantia nigra was significantly reduced by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ.
These results suggest that not only does 3-Me-N-proTIQ have potential as a candidate compound for disease-modifying therapy for PD, but also the N-propargyl functional group plays an important role in neuroprotection.
司来吉兰是一种治疗帕金森病（PD）的药物，其结构类似于内源性帕金森病相关化合物 1,2,3,4-四氢异喹啉（TIQ）。在本研究中，我们评估了 3-甲基-TIQ（3-MeTIQ）和 3-甲基-N-丙炔基-TIQ（3-Me-N-proTIQ）这两种司来吉兰类似 TIQ 衍生物对预防 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠帕金森样症状的作用。
我们评估了 3-MeTIQ 和 3-Me-N-proTIQ 对 MPTP 诱导的运动迟缓以及纹状体多巴胺（DA）和黑质酪氨酸羟化酶（TH）阳性细胞耗竭的预防作用。
除高剂量组外，3-MeTIQ 预处理对 MPTP 诱导的运动迟缓无影响。然而，3-Me-N-proTIQ 预处理显著预防了这种运动不能状态的出现。3-Me-N-proTIQ 以剂量依赖性方式显著预防了 MPTP 诱导的纹状体 DA 和 3,4-二羟基苯乙酸减少，但 3-MeTIQ 则不然。另一方面，3-MeTIQ 处理增加了纹状体中 5-羟色胺及其代谢物 5-羟吲哚乙酸的水平。此外，3-Me-N-proTIQ 预处理显著减少了 MPTP 诱导的黑质 TH 阳性细胞减少，但 3-MeTIQ 则不然。
这些结果表明，3-Me-N-proTIQ 不仅具有作为 PD 疾病修饰治疗候选化合物的潜力，而且 N-丙炔基官能团在神经保护中也起着重要作用。
