(Stroke. 1998;29:2600-2606.)
© 1998 American Heart Association, Inc.
Original Contributions |
Expression and Vascular Effects of Cyclooxygenase-2 in Brain
From the Departments of Anesthesia (J.E.B.), Pathology (S.A.M.), and Internal Medicine and Pharmacology, Cardiovascular Center (F.M.F.), University of Iowa College of Medicine, Iowa City.
Correspondence to J.E. Brian, Jr, MD, Department of Anesthesia 6 JCP, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail eddie-brian{at}uiowa.edu
Background and Purpose—Cyclooxygenase-2 (COX-2) is an inducible isoform of cyclooxygenase. Several types of brain cells in culture can express COX-2 when treated with lipopolysaccharide (LPS) or some cytokines. LPS produces dilatation of cerebral arterioles in vivo through a mechanism that is partially inhibited by indomethacin. In the present study we examined the hypothesis that LPS causes increased expression of COX-2 in brain as well as COX-2–dependent dilatation of cerebral arterioles.
Methods—Cranial windows were implanted in anesthetized rats and used to measure diameter of cerebral arterioles under control conditions and during topical application of various agonists and antagonists. Windows were flushed every 30 minutes for 4 hours with vehicle (artificial cerebrospinal fluid; n=5), LPS (100 ng/mL; n=8), LPS and NS-398 (100 µmol/L; n=8), a selective inhibitor of COX-2, or LPS and dexamethasone (1 µmol/L; n=5), which attenuates expression of COX-2. To examine expression of COX-2 protein in vivo, other animals were injected intracisternally with artificial cerebrospinal fluid (n=3) or LPS (40 ng; n=4). Four hours after injection, the leptomeninges were harvested and analyzed by Western blot for expression of COX-2 protein. In a third group of experiments, COX-2 expression and prostaglandin E2 (PGE2) production were determined in leptomeningeal tissue treated for 4 hours ex vivo with vehicle (n=4), LPS (100 ng/mL; n=4), LPS and NS-398 (100 µmol/L; n=4), or LPS and dexamethasone (1 µmol/L; n=4).
Results—LPS caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 55±9% (mean±SEM) at 4 hours. Coapplication of either NS-398 or dexamethasone with LPS reduced dilatation of cerebral arterioles at hours 2 through 4 (P<0.05). In contrast, NS-398 did not inhibit dilatation of cerebral arterioles in response to bradykinin or ADP. In animals injected intracisternally with vehicle, COX-2 protein was expressed at a very low level in leptomeningeal tissue. Intracisternal injection of LPS increased COX-2 protein expression by approximately 20-fold (P<0.05). In leptomeningeal tissue treated ex vivo with LPS, there was also expression of COX-2. Both dexamethasone and NS-398 markedly reduced COX-2 protein expression in ex vivo LPS-treated tissue. PGE2 production was detectable under control conditions in leptomeningeal tissue incubated in vehicle ex vivo for 4 hours (6.5±1.1 pmol/mg protein). LPS treatment significantly increased PGE2 production to 12.8±1.1 pmol/mg protein (P<0.05). Both dexamethasone and NS-398 significantly attenuated LPS-induced PGE2 production (P<0.05).
Conclusions—LPS increased expression of COX-2 protein in leptomeningeal tissue and caused COX-2–dependent dilatation of cerebral arterioles in vivo. Ex vivo, both NS-398 and dexamethasone suppressed LPS-induced PGE2 production and COX-2 expression in leptomeningeal tissue. Inhibition of LPS-induced dilatation of cerebral arterioles in vivo by NS-398 and dexamethasone suggests that the dilatation was dependent on expression and activity of COX-2. These findings support the concept that exposure of brain to LPS causes cerebral vasodilatation that is dependent in part on expression and activity of COX-2.
Editorial Comment
Associate Editor for Basic Science, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia
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