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 10 mg/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.

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

“…However, translating the anti-inflammatory strategies to clinical uses is challenging and necessitates extra caution partially due to the complexity of inflammatory networks that are concurrently regulated by an array of components and signals that often reinforce each other. Combined therapies targeting multiple key proinflammatory molecules provide comprehensive suppression of inflammatory networks and thus might lead to more consistent and promising therapeutic outcomes (Figure 6) [119, 120, 160, 161]. Compared to biological drugs, brain-permeable small molecules are more realistic candidate agents for this therapeutic strategy due to their advantages in production, delivery and pharmacokinetics, and represent a future direction of developing novel therapeutics for epilepsy.…”

“…For instance, natural product flavonoids containing baicalin and catechin show neuroprotection during kainate-induced excitotoxicity via reducing both COX-2 and 5-LOX activities [119]. Likewise, licofelone (Figure 1), a dual COX/LOX small-molecule inhibitor, which recently was approved as an effective treatment for osteoarthritis, shows anticonvulsant effect in a mouse pentylenetetrazol seizure model [120]. …”

Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide

“…In experiments investigating the possible role of NO pathway in the licofelone central effects, LArg, a NO purcursor; L-NAME, a non-specific NOS inhibitor; AG, a specific iNOS inhibitor; 7-NI, a preferential neuronal NO synthase inhibitor, or the vehicles were administered 15 min before licofelone administration. The dosages and timing of drugs administrations in the present study were based upon prior reports (38)(39)(40).…”

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

“…These natural compounds can efficiently suppress mPGES-1 activity (IC50 = 0.3–10 μM) and reduce PGE 2 levels (Korotkova and Jakobsson, 2014). In addition, licofelone as an mPGES-1 inhibitor has succeeded in reaching the required criteria in phase III clinical trials for treating osteoarthritis (Payandemehr et al, 2015). Pharmacodynamic studies in various animal models have confirmed the effectiveness of licofelone in many types of diseases, such as anti-asthmatic and anticonvulsant effects (Rotondo et al, 2002; Kulkarni and Singh, 2007; Payandemehr et al, 2015).…”