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Mechanistic comparison between MPTP and rotenone neurotoxicity in mice.
NeuroToxicology ( IF 3.4 ) Pub Date : 2018-12-31 , DOI: 10.1016/j.neuro.2018.12.009
Sunil Bhurtel 1 , Nikita Katila 1 , Sunil Srivastav 1 , Sabita Neupane 1 , Dong-Young Choi 1
Affiliation  

Animal models for Parkinson's disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. These results suggest that MPTP-induced dopaminergic neurotoxicity is more acute and specific in comparison to rotenone toxicity, and compensatory brain-derived neurotrophic factor (BDNF) induction and AMPK activation in the rotenone-treated brain might suppress the neuronal injury.

中文翻译:

小鼠MPTP和鱼藤酮神经毒性的机理比较。

帕金森氏病(PD)的动物模型对于了解PD的发病机理和筛选新的治疗方法非常有用。1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)和鱼藤酮是用于开发实验性PD模型的常见神经毒素,均抑制线粒体的复合物I。这被认为是PD中多巴胺能神经变性的一种机制。在这项研究中,我们用MPTP(30 mg / kg /天)或鱼藤酮(2.5 mg / kg /天)治疗小鼠1周,并比较了这些毒素的神经毒性作用。如多巴胺能神经元的丧失,纹状体多巴胺的耗竭,黑质纹状体途径中神经胶质细胞的活化和行为障碍所示,MPTP清楚地在黑质和纹状体中产生了多巴胺能性病变。相比之下,鱼藤酮治疗在黑质纹状体途径中未显示任何明显的神经元损伤,但仅在海马体中引起神经变性和神经胶质活化。MPTP对海马没有这种有害作用,表明海马对鱼藤酮的敏感性高于对MPTP的敏感性。有趣的是,鱼藤酮引起神经营养因子及其下游PI3K-Akt通路的上调,以及腺苷单磷酸激活的蛋白激酶(AMPK)的激活。这些结果表明,与鱼藤酮毒性相比,MPTP诱导的多巴胺能神经毒性更为急性和特异,鱼藤酮治疗的大脑中的补偿性脑源性神经营养因子(BDNF)诱导和AMPK激活可能会抑制神经元损伤。但是它仅在海马中引起神经变性和神经胶质激活。MPTP对海马没有这种有害作用,表明海马对鱼藤酮的敏感性高于对MPTP的敏感性。有趣的是,鱼藤酮引起神经营养因子及其下游PI3K-Akt通路的上调,以及腺苷单磷酸激活的蛋白激酶(AMPK)的激活。这些结果表明,与鱼藤酮毒性相比,MPTP诱导的多巴胺能神经毒性更为急性和特异,鱼藤酮治疗的大脑中的补偿性脑源性神经营养因子(BDNF)诱导和AMPK激活可能会抑制神经元损伤。但它仅在海马中引起神经变性和神经胶质激活。MPTP对海马没有这种有害作用,表明海马对鱼藤酮的敏感性高于对MPTP的敏感性。有趣的是,鱼藤酮引起神经营养因子及其下游PI3K-Akt通路的上调,以及腺苷单磷酸激活的蛋白激酶(AMPK)的激活。这些结果表明,与鱼藤酮毒性相比,MPTP诱导的多巴胺能神经毒性更为急性和特异,鱼藤酮治疗的大脑中的补偿性脑源性神经营养因子(BDNF)诱导和AMPK激活可能会抑制神经元损伤。MPTP对海马没有这种有害作用,表明海马对鱼藤酮的敏感性高于对MPTP的敏感性。有趣的是,鱼藤酮引起神经营养因子及其下游PI3K-Akt通路的上调,以及腺苷单磷酸激活的蛋白激酶(AMPK)的激活。这些结果表明,与鱼藤酮毒性相比,MPTP诱导的多巴胺能神经毒性更为急性和特异,鱼藤酮治疗的大脑中的补偿性脑源性神经营养因子(BDNF)诱导和AMPK激活可能会抑制神经元损伤。MPTP对海马没有这种有害作用,表明海马对鱼藤酮的敏感性高于对MPTP的敏感性。有趣的是,鱼藤酮引起神经营养因子及其下游PI3K-Akt通路的上调,以及腺苷单磷酸激活的蛋白激酶(AMPK)的激活。这些结果表明,与鱼藤酮毒性相比,MPTP诱导的多巴胺能神经毒性更为急性和特异,鱼藤酮治疗的大脑中的补偿性脑源性神经营养因子(BDNF)诱导和AMPK激活可能会抑制神经元损伤。
更新日期:2018-12-31
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