Thakur Poonam, Nehru Bimla
Department of Biophysics, Panjab University, Chandigarh 160014, India.
Neuropharmacology. 2014 Apr;79:190-200. doi: 10.1016/j.neuropharm.2013.11.016. Epub 2013 Dec 1.
Protein aggregation and dysfunction of ubiquitin proteasome system (UPS) have been implicated in Parkinson's disease (PD) pathology for a long time. Heat shock proteins (HSPs) have neuro-protective effects in PD as they assist in protein refolding and targeting of irreparable proteins to UPS. To realize their benefits in a chronically progressing disease like PD, it is imperative to maintain slightly up-regulated levels of HSPs consistently over a longer period of time. Here, we evaluate the possible beneficial effects of HSP inducer carbenoxolone (cbx) in a rotenone-based rat model of PD. Simultaneously with rotenone, a low dose of cbx (20 mg/kg body weight) was administered for five weeks to male SD rats. Weekly behavioral analysis along with end-point evaluation of HSPs, UPS activity, apoptosis, and oxidative stress were performed. The activation of heat shock factor-1 (HSF-1) and up-regulation of HSP70, HSP40, and HSP27 levels in mid-brain following cbx administration resulted in the reduction of α-synuclein and ubiquitin aggregation. This decrease seems to be mediated by reduction in protein carbonylation as well as up-regulation of UPS activity. In addition, the decrease in apoptosis and oxidative stress following HSP upregulation prevented the decline in tyrosine hydroxylase (TH) and dopamine levels in mid-brain region, which in turn resulted in improved motor functions. Thus, persistent HSP induction at low levels by cbx could improve the PD pathophysiology.
蛋白质聚集和泛素蛋白酶体系统（UPS）功能障碍长期以来一直被认为与帕金森病（PD）的病理过程有关。热休克蛋白（HSPs）在PD中具有神经保护作用，因为它们有助于蛋白质重新折叠并将无法修复的蛋白质靶向UPS。为了在像PD这样的慢性进展性疾病中实现其益处，必须在较长时间内持续维持HSPs水平略有上调。在此，我们评估了HSP诱导剂甘珀酸（cbx）在基于鱼藤酮的PD大鼠模型中的可能有益作用。在给雄性SD大鼠注射鱼藤酮的同时，给予低剂量的cbx（20 mg/kg体重），持续5周。每周进行行为分析，并对HSPs、UPS活性、细胞凋亡和氧化应激进行终点评估。给予cbx后，中脑中热休克因子-1（HSF-1）的激活以及HSP70、HSP40和HSP27水平的上调导致α-突触核蛋白和泛素聚集减少。这种减少似乎是由蛋白质羰基化的减少以及UPS活性的上调介导的。此外，HSP上调后细胞凋亡和氧化应激的减少阻止了中脑区域酪氨酸羟化酶（TH）和多巴胺水平的下降，进而改善了运动功能。因此，cbx在低水平持续诱导HSPs可以改善PD的病理生理过程。
