Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors
Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors
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DOI：
10.1111/bph.13208
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发表时间：
2015-08-01
影响因子：
7.3
通讯作者：
Dexter, David T.
中科院分区：
文献类型：
--
作者：
Harrison, Ian F.;Crum, William R.;Dexter, David T.
背景和目的组蛋白低乙酰化与帕金森病（Parkinson's disease，PD）相关，可能是由于负责组蛋白乙酰化（去乙酰化）的酶活性失衡所致;纠正组蛋白低乙酰化可能具有神经保护/神经修复作用。使用抗癫痫药物丙戊酸钠，一种已知的组蛋白去乙酰化酶抑制剂（HDACI），利用延迟开始的研究设计，在lactacystin大鼠模型PD.Experimental ApproachThe不可逆的蛋白酶体抑制剂lactacystin单侧注射到黑质的Sprague-Dawley大鼠，随后接受丙戊酸盐28天，从lactacystin损伤后7天开始。纵向运动行为测试，结构MRI和黑质纹状体完整性的死后评估被用来跟踪PD模型的变化，并量化神经保护/恢复。随后进行细胞和分子分析，以阐明潜在的机制丙戊酸盐的effects.Key ResultsDespite生产的结构重建在健康和lactacystin-lesioned大脑的一个独特的模式，延迟启动丙戊酸盐管理诱导剂量依赖性神经保护/恢复对lactacystin神经毒性，其特征在于运动缺陷缓解，脑形态学改变的减弱和黑质中多巴胺能神经元的恢复。分子分析显示，丙戊酸盐减轻lactacystin诱导的组蛋白hypoacetylation和诱导上调脑神经营养/神经保护factors. Conclusionsand上调的神经营养/神经保护因子与丙戊酸盐治疗最终在神经保护和neurorestorative表型在这个动物模型的PD。由于丙戊酸盐诱导大脑结构重塑，需要进一步研究以确定丙戊酸盐是否代表疾病治疗的可行候选药物;然而，结果表明HDACI可能具有作为PD疾病修饰剂的潜力。
Background and PurposeHistone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD.Experimental ApproachThe irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague-Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects.Key ResultsDespite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors.Conclusions and ImplicationsThe histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that HDACIs could hold potential as disease-modifying agents in PD.