Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons

Enid T. McKinley, Timothy C. Baranowski, Delali O. Blavo, Candace Cato, Thanh N. Doan, Amy L. Rubinstein
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引用次数: 175

Abstract

Parkinson's disease is characterized by a severe loss of dopaminergic neurons resulting in a range of motor deficits. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain with corresponding Parkinsonian symptoms. Several animal species have also shown sensitivity to MPTP, including primates, mice, goldfish, and, most recently, zebrafish. This study demonstrates that the effect of MPTP on dopaminergic neurons in zebrafish larvae is mediated by the same pathways that have been demonstrated in mammalian species. MPTP-induced neurodegeneration was prevented by co-incubation with either the monoamine oxidase-B (MAO-B) inhibitor l-deprenyl or the dopamine transporter (DAT) inhibitor nomifensine. Furthermore, targeted inactivation of the DAT gene by antisense morpholinos also protected neurons from MPTP damage. Thus, the mechanism for MPTP-induced dopaminergic neuron toxicity in mammals is conserved in zebrafish larvae. Effects on swimming behavior and touch response that result from MPTP damage are partially ameliorated by both l-deprenyl and DAT knockdown.

mptp对斑马鱼多巴胺能神经元毒性的神经保护作用
帕金森病的特点是多巴胺能神经元严重丧失,导致一系列运动缺陷。已知神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)可导致人类中脑多巴胺能神经元的类似丧失,并伴有相应的帕金森症状。一些动物物种也表现出对MPTP的敏感性,包括灵长类动物、老鼠、金鱼,以及最近发现的斑马鱼。本研究表明,MPTP对斑马鱼幼体多巴胺能神经元的影响是通过与哺乳动物相同的途径介导的。此外,反义morpholinos对DAT基因的靶向失活也可以保护神经元免受MPTP损伤。因此,mptp诱导哺乳动物多巴胺能神经元毒性的机制在斑马鱼幼虫中是保守的。MPTP损伤对游泳行为和触觉反应的影响可通过l-去戊烯基和DAT的敲除得到部分改善。
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