Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A30P mutant alpha-synuclein
Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A30P mutant alpha-synuclein
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DOI：
10.14670/hh-28.999
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发表时间：
2013-08-01
影响因子：
2
通讯作者：
Castro, R.
中科院分区：
文献类型：
--
作者：
Brito-Armas, J. M.;Baekelandt, V.;Castro, R.
帕金森病（PD）的两个标志是多巴胺能细胞损失和细胞质内含物（路易体）的存在。α-突触核蛋白（Lewy小体的主要成分）中的不同点突变已在家族性PD中被鉴定。α-突触核蛋白也是散发性PD病例中路易体的主要成分之一。此外，氧化应激和线粒体损伤和多巴胺代谢产生的自由基被认为在PD发病机制中起关键作用。褪黑激素是一种已知的由松果体分泌的有效抗氧化剂，可以保护免受与线粒体功能的进行性损害和氧化损伤增加相关的几种致帕金森病化合物的影响。然而，褪黑激素的神经保护作用从未在基于突变的α-突触核蛋白的病毒表达的新的PD遗传模型中进行过测试。将编码A30 P突变体人α-突触核蛋白（lenti-A30 P）的慢病毒载体立体定向注射到成年雄性Sprague-Dawley大鼠的右侧黑质中，并通过从黑质施用lenti-A30 P前两天直至注射后8周施用褪黑激素或载体来检查神经保护作用。结果发现，与注射lenti-eGFP的对侧相比，lenti-A30 P在内侧和外侧黑质中都诱导了显著的TH+细胞损失。然而，褪黑激素给药在黑质的两个区域显示出总的神经保护作用。总之，这里的数据表明，褪黑激素对黑质中突变体α-突触核蛋白诱导的损伤具有神经保护作用。
Two hallmarks of Parkinson's disease (PD) are dopaminergic cell loss and the presence of cytoplasmic inclusions (Lewy bodies). Different point mutations in alpha-synuclein, the main constituent of Lewy bodies, have been identified in familial PD. Alpha-synuclein also constitutes one of the main components of Lewy bodies in sporadic cases of PD. Moreover, oxidant stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiopathogenesis. Melatonin, a known potent antioxidant secreted by the pineal gland, may protect against the effect of several Parkinsonogenic compounds that are associated with progressive impairment of mitochondrial function and increased oxidative damage. However, the neuroprotective effect of melatonin has never been tested in the newly available genetic models of PD based on the viral expression of mutated alpha-synuclein. Lentiviral vectors encoding A30P mutant human alpha-synuclein (lenti-A30P) were stereotactically injected into the right substantia nigra of adult male Sprague-Dawley rats and neuroprotection was examined by administration of melatonin or vehicle from two days before nigral administration of lenti-A30P until eight weeks after injection. It was found that lenti-A30P induced a significant TH+ cell-loss both in the medial and lateral substantia nigra versus the contrallateral side injected with lenti-eGFP. However, melatonin administration showed a total neuroprotective effect in both regions of the substantia nigra. In conclusion, the data here show that melatonin is neuroprotective against mutant alpha-synuclein-induced injury in the substantia nigra.