title: Targeting oxidative stress, mitochondrial dysfunction and neuroinflammatory signaling by selective cyclooxygenase (COX)-2 inhibitors mitigates MPTP-induced neurotoxicity in mice.
abstract: Several studies have pointed towards the role of oxidative stress, mitochondrial dysfunction and neuroinflammation in Parkinson's disease (PD). The present study was focused on the possible neuroprotective effect of selective cyclooxygenase (COX)-2-inhibitors: valdecoxib and NS-398 in 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP)-induced neurotoxicity in mice. MPTP administration in dose of 40 mg/kg, i.p (four injections of 10mg/kg, i.p. at an interval of 1h each) significantly induced the Parkinson-like symptoms in mice as indicated by change in locomotor activity, inability to correct posture (bar test), and oxidative stress (increased levels of lipid peroxidation, nitrite concentration, and depletion of antioxidant enzyme). MPTP administration significantly impaired mitochondrial complex-I activity and redox activity, upregulated the caspase-3 and NF-κB levels as compared to vehicle group. Treatment with valdecoxib (5 or 10 mg/kg, p.o.) or NS-398 (5 or 10mg/kg, p.o.) for 7 days significantly reversed behavioral, biochemical, mitochondrial complex alterations as well as attenuated the induction of proinflammatory mediators in MPTP-treated groups. The findings of the present study substantiate the neuroprotective role of selective COX-2 inhibitors in ameliorating MPTP-induced neurodegeneration in mice and suggest the possible therapeutic potential of these drugs in the management of PD.
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: S K
authors.initials: SK
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002389:Catatonia / Q000523:psychology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000378:metabolism; D018696:Neuroprotective Agents; D009573:Nitrites / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013778:Tetrazolium Salts; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053148:Caspase 3; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D008315:Malondialdehyde; D009245:NADH Dehydrogenase; D018696:Neuroprotective Agents; D009573:Nitrites; D009578:Nitrobenzenes; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D013778:Tetrazolium Salts; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances; D051996:Transcription Factor RelA; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C406224:valdecoxib; D000096926:Benzenesulfonamides; C022616:thiazolyl blue