title: 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.affiliation: Pharmacology Division, UGC Centre of Advanced Study (UGC-CAS), University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
authors.forename: Jitendriya
authors.initials: J
authors.lastname: Mishra
authors.forename: Tanya
authors.initials: T
authors.lastname: Chaudhary
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006816:Huntington Disease; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D017378:Quinolinic Acid; D017208:Rats, Wistar; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D014635:Valproic Acid; D006655:Histone Deacetylases; D017378:Quinolinic Acid