Involvement of Cycloxygenase-1 and -2 in Ocular Inflammation and Pain Using a Rabbit Model

Abstract

Purpose:: Bromfenac sodium (BF) is a potent inhibitor of both cyclooxygenase-1 and -2 (COX-1 and COX-2) and nimesulide (NS) is a selective COX-2 inhibitor. To evaluate BF and NS in the inhibition of COX-1 and COX-2 using various ocular inflammation and ocular pain severities in a rabbit model.

Methods:: Dutch belted rabbits were used and test drugs were prepared 0.1% ophthalmic solution. Inflammation model: a) Paracentesis: One hundred fifty µl of aqueous humor was aspirated with a 30 gauge syringe at 1 hr after instillation of one drop of test agent. The aqueous flare was measured with a flare cell meter (Kowa) for 3 hrs. b) Laser irradiation: The iris was irradiated at 6 spots equally spaced by argon laser at 1 hr after instillation of test agent and the aqueous flare was measured for 3 hrs. Pain model: a) Corneal sensitivity: The sensitivity of central cornea was evaluated using a Cochet-Bonnet esthesiometer for 3 hrs after instillation of test agent using oxybuprocaine 0.4% as the comparison. b) Chemical stimuli: Sodium hydroxide was applied to the cornea after instillation of test agent using oxybuprocaine 0.4% as the comparison and the distance between upper and lower palpebral fissure (mm) was measured by a caliper for 5 hrs.

Results:: BF inhibited the increase in aqueous protein production induced by paracentesis by 95%, whereas, NS exhibited no inhibitory activity. Laser irradiation gradually increased aqueous protein production with a peak at 1 hr. BF and NS demonstrated significant inhibitory activities in aqueous protein production by 88% and 58%, respectively. Oxybuprocaine 0.4% removed corneal sensitivity completely and BF reduced the corneal sensitivity threshold by 50% compared to oxybuprocaine. NS had no effect on the normal corneal sensitivity. Oxybuprocaine 0.4% did not show significant effect against sodium hydroxide-induced pain. In contrast, BF significantly reduced the ocular pain by 50% during 5 hrs.

Conclusions:: This study suggests that COX-1 responds acutely to direct mechanical stimulation of the eye. COX-2 is involved in moderate to severe inflammation and chemical burn-induced ocular pain. COX-2 demonstrates chronic responsiveness. Therefore, NSAIDs with equivalent inhibition in both COX-1 and COX-2 could potentially treat various mild to severe ocular inflammation and ocular pain conditions.

Keywords: inflammation • aqueous • ocular irritants