Inhibition of Neuroinflammation and Mitochondrial Dysfunctions by Carbenoxolone in the Rotenone Model of Parkinson's Disease
Inhibition of Neuroinflammation and Mitochondrial Dysfunctions by Carbenoxolone in the Rotenone Model of Parkinson's Disease
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DOI：
10.1007/s12035-014-8769-7
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发表时间：
2015-02-01
影响因子：
5.1
通讯作者：
Nehru, Bimla
中科院分区：
文献类型：
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作者：
Thakur, Poonam;Nehru, Bimla
α-突触核蛋白聚集以多种方式促进帕金森病（PD）病理学-最重要的两种是神经炎症和线粒体功能障碍的激活。我们最近的研究表明，热休克蛋白（HSP）诱导剂，甘珀酸（Cbx），在减少α-突触核蛋白的聚集在鱼藤酮为基础的PD大鼠模型的有益效果。本研究旨在探讨其减弱α-突触核蛋白介导的神经炎症和线粒体功能改变的能力。PD模型是通过施用鱼藤酮（2 mg/kg b.wt.）雄性SD大鼠5周。Cbx（20 mg/kg体重）发现共同给药减少了鱼藤酮引起的星形胶质细胞的活化。随后，促炎细胞因子TNF-α、IL-6和IL-1 β的释放受到抑制。此外，在Cbx共同治疗后，各种炎症介质如考克斯-2、iNOS和NF-κ B的表达水平也降低。Cbx也被证明可以减少鱼藤酮诱导的线粒体复合物-I，-II和-IV活性的下降。线粒体功能的保护和神经炎症的减少导致ROS的产生减少，随后减少氧化应激。这反映在细胞溶质和线粒体GSH水平以及SOD活性的增加，在Cbx共处理。因此，Cbx通过减少α-突触核蛋白聚集来减少炎症反应并改善线粒体功能障碍。此外，它还可以减少相关的氧化应激。由于其靶向PD中涉及的多种途径的能力，Cbx可以作为一种非常有益的预防剂。
alpha-Synuclein aggregation contributes to the Parkinson's disease (PD) pathology in multiple ways-the two most important being the activation of neuroinflammation and mitochondrial dysfunction. Our recent studies have shown the beneficial effects of a heat shock protein (HSP) inducer, carbenoxolone (Cbx), in reducing the aggregation of alpha-synuclein in a rotenone-based rat model of PD. The present study was designed to explore its ability to attenuate the alpha-synuclein-mediated alterations in neuroinflammation and mitochondrial functions. The PD model was generated by the rotenone administration (2 mg/kg b.wt.) to the male SD rats for a period of 5 weeks. Cbx (20 mg/kg b.wt.) co-administration was seen to reduce the activation of astrocytes incited by rotenone. Subsequently, the release of pro-inflammatory cytokines TNF-alpha, IL-6, and IL-1 beta was inhibited. Further, the expression level of various inflammatory mediators such as COX-2, iNOS, and NF-kappa B was also reduced following Cbx co-treatment. Cbx was also shown to reduce the rotenone-induced decline in activity of mitochondrial complexes-I, -II, and -IV. Protection of mitochondrial functions and reduction in neuroinflammation lead to the lesser production of ROS and subsequently reduced oxidative stress. This was reflected by the increase in both the cytosolic and mitochondrial GSH levels as well as SOD activity during Cbx co-treatment. Thus, Cbx reduces the inflammatory response and improves the mitochondrial dysfunctions by reducing alpha-synuclein aggregation. In addition, it also reduces the associated oxidative stress. Due to its ability to target the multiple pathways implicated in the PD, Cbx can serve as a highly beneficial prophylactic agent.