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Inhibition of Neuroinflammation and Mitochondrial Dysfunctions by Carbenoxolone in the Rotenone Model of Parkinson’s Disease

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Abstract

α-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 α-synuclein in a rotenone-based rat model of PD. The present study was designed to explore its ability to attenuate the α-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-α, IL-6, and IL-1β was inhibited. Further, the expression level of various inflammatory mediators such as COX-2, iNOS, and NF-κB 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 α-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.

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Acknowledgments

The study was carried out with the funds provided by Department of Science and Technology (DST), India.

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  1. Department of Biophysics, Panjab University, Chandigarh, 160014, India

    Poonam Thakur & Bimla Nehru

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  1. Poonam Thakur
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Correspondence to Bimla Nehru.

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Thakur, P., Nehru, B. Inhibition of Neuroinflammation and Mitochondrial Dysfunctions by Carbenoxolone in the Rotenone Model of Parkinson’s Disease. Mol Neurobiol 51, 209–219 (2015). https://doi.org/10.1007/s12035-014-8769-7

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