Rosiglitazone synergizes the neuroprotective effects of valproic acid against quinolinic acid-induced neurotoxicity in rats: targeting PPARγ and HDAC pathways.

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.

• Authors: Jitendriya Mishra, Tanya Chaudhary, Anil Kumar
• Journal: Neurotoxicity research (Neurotox Res) Vol. 26 Issue 2 Pg. 130-51 (Aug 2014) ISSN: 1476-3524 [Electronic] United States
• PMID: 24566814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Neuroprotective Agents
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Valproic Acid
• Histone Deacetylases
• Quinolinic Acid

Topics

• Animals
• Body Weight (drug effects)
• Brain (drug effects, pathology, physiopathology)
• Disease Models, Animal
• Drug Synergism
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Huntington Disease
• Male
• Maze Learning (drug effects, physiology)
• Motor Activity (drug effects, physiology)
• Neurodegenerative Diseases (drug therapy, pathology, physiopathology)
• Neuroprotective Agents (pharmacology)
• Neurotoxicity Syndromes (drug therapy, pathology, physiopathology)
• PPAR gamma (agonists, metabolism)
• Quinolinic Acid
• Rats, Wistar
• Rosiglitazone
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)
• Valproic Acid (pharmacology)