Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence.
Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.
Gupta
Amit
A
Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study (UGC-CAS), Punjab University, Chandigarh, India.
Kumar
Anil
A
Kulkarni
S K
SK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015227:Lipid Peroxidation; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D020267:MPTP Poisoning / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009573:Nitrites; D011758:Pyrroles; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D053148:Caspase 3; C088092:licofelone