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

Authors
  • Mishra, Jitendriya1
  • Chaudhary, Tanya1
  • Kumar, Anil1
  • 1 Panjab University, Pharmacology Division, UGC Centre of Advanced Study (UGC-CAS), University Institute of Pharmaceutical Sciences, Chandigarh, 160014, India , Chandigarh (India)
Type
Published Article
Journal
Neurotoxicity Research
Publisher
Springer-Verlag
Publication Date
Feb 25, 2014
Volume
26
Issue
2
Pages
130–151
Identifiers
DOI: 10.1007/s12640-014-9458-z
Source
Springer Nature
Keywords
License
Yellow

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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