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Rosiglitazone Synergizes the Neuroprotective Effects of Valproic Acid Against Quinolinic Acid-Induced Neurotoxicity in Rats: Targeting PPARγ and HDAC Pathways

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Abstract

Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder which affects medium spiny GABAergic neurons mainly in the striatum. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation, and signaling of neurotrophic factors are some of the common cellular pathways involved in HD. Quinolinic acid (QA) causes excitotoxicity by stimulating N-methyl-d-aspartate receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-γ (PPARγ) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid (VPA) and its interaction with rosiglitazone against QA induced HD-like symptoms in rats. Single bilateral intrastriatal QA (200 nmol/2 μl saline) administration significantly caused motor incoordination, memory impairment, oxidative damage, mitochondrial dysfunction (complex I, II, II and IV), cellular alterations [tumor necrosis factor-alpha (TNF-α), caspase-3, brain derived neurotrophic factor, acetylcholinesterase], and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/kg) and VPA (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical, and cellular alterations as compared to control (QA 200 nmol) group. However, VPA (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergized their neuroprotective effect, which was significant as compared to their effects per se in QA-treated animals. The present study provides an evidence of possible interplay of PPARγ agonists and HDAC inhibitors as a novel therapeutic strategy in the management of HD.

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Acknowledgments

The Major Research Project sanctioned to Professor Anil Kumar by University Grants Commission (UGC), New Delhi is gratefully acknowledged. Mr. Jitendriya Mishra is the project fellow in this project.

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The authors have no competing financial interests to declare. There is no conflict of interest between any of the authors.

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  1. Pharmacology Division, UGC Centre of Advanced Study (UGC-CAS), University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    Jitendriya Mishra, Tanya Chaudhary & Anil Kumar

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  1. Jitendriya Mishra
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Mishra, J., Chaudhary, T. & Kumar, A. Rosiglitazone Synergizes the Neuroprotective Effects of Valproic Acid Against Quinolinic Acid-Induced Neurotoxicity in Rats: Targeting PPARγ and HDAC Pathways. Neurotox Res 26, 130–151 (2014). https://doi.org/10.1007/s12640-014-9458-z

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