A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice.

Abstract

Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of licofelone as a potential therapeutic agent, we studied the effect of licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.