title: Synergistical neuroprotection of rofecoxib and statins against malonic acid induced Huntington's disease like symptoms and related cognitive dysfunction in rats.
abstract: Malonic acid (MA) is a reversible inhibitor of succinate dehydrogenase (SDH) which induces mitochondrial dysfunction followed by secondary excitotoxicity and apoptosis due to generation of reactive oxygen species. Therapeutic potential of rofecoxib and statins have been well documented in several experimental models of neurodegenerative disorders, however, its exact mechanism of action is not known properly. Therefore, the present study is an attempt to investigate the effect of rofecoxib along with the statins against MA induced behavioural and biochemical alterations in rats. Single intrastriatal MA (6 µmol) significantly caused motor incordination, memory dysfunction and alteration in the antioxidant enzyme levels, mitochondrial enzyme complex (I, II, IV) activities, mitochondrial redox ratio and pro-inflammatory cytokine [tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] levels in the striatum as compared to the naive group. Fourteen days treatment with rofecoxib, atorvastatin, simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to control (MA treated group). However, the treatment of rofecoxib along with atorvastatin or simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to their individual effects. The results of the present study demonstrated that rofecoxib modulates the protective effects of statins against MA-induced neurobehavioral and related biochemical and cellular alterations in rats. This further provides evidence toward the involvement of neuroinflammatory cascade in the pathogenesis of Huntington's disease.
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh 160014, India. kumaruips@yahoo.com
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Neha
authors.initials: N
authors.lastname: Sharma
authors.forename: Jitendriya
authors.initials: J
authors.lastname: Mishra
authors.forename: Harikesh
authors.initials: H
authors.lastname: Kalonia
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D006816:Huntington Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007783:Lactones / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008314:Malonates; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D008314:Malonates; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D011758:Pyrroles; D013450:Sulfones; C116926:rofecoxib; C030290:malonic acid; D000069059:Atorvastatin; D019821:Simvastatin