Abstract

1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) is a neurotoxin that damages dopaminergic neurons. Zebrafish has been shown to be a suitable model organism to investigate the molecular pathways in the pathogenesis of Parkinson’s disease and also for potential therapeutic agent research. Boron has been shown to play an important role in the neural activity of the brain. Boronic acids are used in combinatorial approaches in drug design and discovery. The effect of 3-pyridinylboronic acid which is an important sub-class of heterocyclic boronic acids has not been evaluated in case of MPTP exposure in zebrafish embryos. Accordingly, this study was designed to investigate the effects of 3-pyridinylboronic acid on MPTP exposed zebrafish embryos focusing on the molecular pathways related to neurodegeneration and apoptosis by RT-PCR. Zebrafish embryos were exposed to MPTP (800 μM); MPTP + Low Dose 3-Pyridinylboronic acid (50 μM) (MPTP + LB) and MPTP + High Dose 3-Pyridinylboronic acid (100 μM) (MPTP + HB) in well plates for 72 hours post fertilization. Results of our study showed that MPTP induced a P53 dependent and Bax mediated apoptosis in zebrafish embryos and 3-pyridinylboronic acid restored the locomotor activity and gene expressions related to mitochondrial dysfunction and oxidative stress due to the deleterious effects of MPTP, in a dose-dependent manner.

摘要

1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是一种损伤多巴胺能神经元的神经毒素。斑马鱼已被证明是一种合适的模式生物，可用于研究帕金森病发病机制中的分子途径以及潜在的治疗剂研究。硼已被证明在大脑的神经活动中发挥重要作用。硼酸用于药物设计和发现的组合方法。3-吡啶基硼酸是杂环硼酸的一个重要亚类，尚未评估斑马鱼胚胎中 MPTP 暴露的影响。因此，本研究旨在通过 RT-PCR 研究 3-吡啶基硼酸对暴露于 MPTP 的斑马鱼胚胎的影响，重点关注与神经变性和细胞凋亡相关的分子途径。斑马鱼胚胎暴露于 MPTP (800 μM)；MPTP + 低剂量 3-吡啶基硼酸 (50 μM) (MPTP + LB) 和 MPTP + 高剂量 3-吡啶基硼酸 (100 μM) (MPTP + HB) 在孔板中受精后 72 小时。我们的研究结果表明，MPTP 在斑马鱼胚胎中诱导 P53 依赖性和 Bax 介导的细胞凋亡，并且由于 MPTP 的有害作用，3-吡啶基硼酸恢复了与线粒体功能障碍和氧化应激相关的运动活性和基因表达，呈剂量依赖性方式。