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INFLAMMATION AND CYTOKINES

Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells

Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Submitted 8 September 2004 ; accepted in final form 20 December 2004

Acetaminophen is a widely used antipyretic and analgesic drug whose mechanism of action has recently been suggested to involve inhibitory effects on prostaglandin synthesis via a newly discovered cyclooxygenase variant (COX-3). Because COX-3 expression is high in cerebral endothelium, we investigated the effect of acetaminophen on the prostaglandin production of cultured rat cerebral endothelial cells (CECs). Acetaminophen dose-dependently inhibited both basal and LPS-induced PGE₂ production in CECs with IC₅₀ values of 15.5 and 6.9 µM, respectively. Acetaminophen also similarly inhibited the synthesis of 6-keto-PGF₁ and thromboxane B₂. LPS stimulation increased the expression of COX-2 but not COX-1 or COX-3. In addition, the selective COX-2 inhibitor NS398 (1 µM) was equally as effective as acetaminophen in blocking LPS-induced PGE₂ production. Acetaminophen did not influence the expression of the three COX isoforms and the inducible nitric oxide synthase. In LPS-stimulated isolated cerebral microvessels, acetaminophen also significantly inhibited PGE₂ production. Our results show that prostaglandin production in CECs during basal and stimulated conditions is very sensitive to inhibition by acetaminophen and suggest that acetaminophen acts against COX-2 and not COX-1 or COX-3. Furthermore, our findings support a critical role for cerebral endothelium in the therapeutic actions of acetaminophen in the central nervous system.

cyclooxygenase-3; enzyme-linked immunosorbent assay; lipopolysaccharide; NS398

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