Pharmacological separation between peripheral and central functions of cyclooxygenase-2 with CIAA, a novel cyclooxygenase-2 inhibitor

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• 作者：Takako Okumura ; Yoko Murata ; Masanori Hizue ; Tomomi Matsuura ; Rie Naganeo ; Yoshihito Kanai ; Akio Murase ; Ayano Sakakibara ; Isami Fujita and Kazunari Nakao
• 关键词：CIAA ; Celecoxib ; Rofecoxib ; COX-2 ; Peripheral
• 刊名：European Journal of Pharmacology
• 出版年：2006
• 出版时间：6 June 2006
• 年：2006
• 卷：539
• 期：1-2
• 页码：125-130
• 全文大小：194 K

文摘

There are many reports concerning the physiological and pathological involvement of cyclooxygenase (COX)-2 in the central nervous system and peripheral tissue cells. Selective COX-2 inhibitors that mainly distribute peripherally have not been reported thus far. Therefore central and peripheral roles of COX-2 remain classified pharmacologically. In this study, in vivo pharmacological profiles of CIAA ([6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid), a novel selective COX-2 inhibitor which distributes at higher concentrations in plasma than in brain, were compared with those of well-known selective COX-2 inhibitors, celecoxib and rofecoxib. Additionally, the possibility of pharmacological separation between peripheral and central actions of COX-2 with the inhibitors was investigated. CIAA selectively inhibited COX-2 activity compared with COX-1 in in vitro assays with rat whole blood. The compound exhibited lower brain penetration and higher plasma concentration (the brain/plasma concentration ratio was approximately 0.02) than celecoxib and rofecoxib after oral administration. Therefore, CIAA is mainly expected to act peripherally. Edema and prostaglandin E₂ (PGE₂) production in Carrageenan-injected rat paws, and pyrexia and PGE₂ production in the brain in lipopolysaccharide (LPS)-injected rats were measured in in vivo experiments. CIAA exhibited lower ratios of anti-pyretic/anti-edematous activities and of inhibitory activities of PGE₂ production in brain/paw than those of celecoxib and rofecoxib, and these ratios well-reflected brain/plasma concentration ratios. In conclusion, we discovered a novel selective COX-2 inhibitor, CIAA, which distributes at higher concentrations in plasma than in brain, which would make possible the pharmacological separation of the peripheral and central functions of COX-2.