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      Differential Inhibition by Nimesulide of the Early and Late Phases of Intravenous- and Intracerebroventricular-LPS-Induced Fever in Guinea Pigs

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          Abstract

          Objectives: The findings that inducible cyclooxygenase (COX)-2, but not constitutive COX-1, is upregulated in the brain of conscious rats ∼1.5 h after intraperitoneal pyrogen administration, that the systemic administration of COX-2 inhibitors abolishes fever, and that COX-2-deficient mice do not develop fever in response to intraperitoneal lipopolysaccharide (LPS) have strongly implicated COX-2 in the mediation of the febrile response. However, the biosynthesis of COX-2 is significantly slower than the onset of the fever produced by intravenously injected LPS. It consequently seems improbable that inducible COX-2 could play a role in the initiation of this febrile response, but a role for COX-1 has not yet been categorically ruled out; or, alternatively, a constitutive isoform of COX-2 could have such a role. We have studied, therefore, the effects of the non-selective COX inhibitor indomethacin, the COX-1-selective inhibitor SC-560, and the COX-2-selective inhibitor nimesulide on the characteristically biphasic fever induced by intravenous LPS in conscious guinea pigs; it has an onset latency of ∼10 min. Methods: We injected the inhibitors 30 min before LPS, in various combinations of doses and routes; their respective vehicles were the control solutions. Core temperatures (T<sub>c</sub>) were monitored continuously, and plasma and brain PGE<sub>2</sub> levels were measured before and at 2-hour intervals after LPS administration. Results: Intraperitoneal indomethacin at 10 mg kg<sup>–1</sup> attenuated both phases of intravenous LPS (2 µg kg<sup>–1</sup>) fever, but the first more so than the second; at 50 mg kg<sup>–1</sup>, it inhibited the febrile response completely. Intraperitoneal SC-560 (5 mg kg<sup>–1</sup>) did not affect the febrile response to intravenous LPS (2 µg kg<sup>–1</sup>). Intraperitoneal nimesulide (0.3, 1.0, and 3.0 mg kg<sup>–1</sup>) dose dependently attenuated intravenous LPS (0.1 and 2 µg kg<sup>–1</sup>) fever; the second phase of the biphasic T<sub>c</sub> rise was affected significantly more than the first. Intraperitoneal nimesulide also prevented the associated rises in plasma and brain PGE<sub>2</sub> levels. Intracerebroventricular LPS (150 ng kg<sup>–1</sup>) evoked a monophasic fever with a long onset latency (∼30 min); it was accompanied by a rise in brain PGE<sub>2</sub> only, implying that the febrigenic PGE<sub>2</sub> was generated directly in the brain. This response, however, was completely abolished by intraperitoneal nimesulide (3 mg kg<sup>–1</sup>), indicating that nimesulide crosses the blood-brain barrier. Intracerebroventricular nimesulide at 0.3 mg kg<sup>–1</sup> prevented the rise in plasma PGE<sub>2</sub> after intravenous LPS (2 µg kg<sup>–1</sup>) and again attenuated the second febrile peak significantly more than the first. Conclusions: COX-1 is not involved in intravenous LPS fever production, and COX-2 appears to play a greater role in the late than in the early phase of intravenous LPS fever in guinea pigs. The involvement of a constitutive COX-2 is inferred in the early phase.

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          Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis.

          Here we report the molecular identification of cytosolic glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (cPGES), a terminal enzyme of the cyclooxygenase (COX)-1-mediated PGE(2) biosynthetic pathway. GSH-dependent PGES activity in the cytosol of rat brains, but not of other tissues, increased 3-fold after lipopolysaccharide (LPS) challenge. Peptide microsequencing of purified enzyme revealed that it was identical to p23, which is reportedly the weakly bound component of the steroid hormone receptor/hsp90 complex. Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol. A tyrosine residue near the N terminus (Tyr(9)), which is known to be critical for the activity of cytosolic GSH S-transferases, was essential for PGES activity. The expression of cPGES/p23 was constitutive and was unaltered by proinflammatory stimuli in various cells and tissues, except that it was increased significantly in rat brain after LPS treatment. cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to produce PGE(2) from exogenous and endogenous arachidonic acid, the latter being supplied by cytosolic phospholipase A(2) in the immediate response. Thus, functional coupling between COX-1 and cPGES/p23 may contribute to production of the PGE(2) that plays a role in maintenance of tissue homeostasis.
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            Pharmacological analysis of cyclooxygenase-1 in inflammation.

            The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.
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              Cloning, expression, and up-regulation of inducible rat prostaglandin e synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis.

              We have cloned and expressed the inducible form of prostaglandin (PG) E synthase from rat and characterized its regulation of expression in several tissues after in vivo lipopoylsaccharide (LPS) challenge. The rat PGE synthase is 80% identical to the human enzyme at the amino acid level and catalyzes the conversion of PGH(2) to PGE(2) when overexpressed in Chinese hamster ovary K1 (CHO-K1) cells. PGE synthase activity was measured using [(3)H]PGH(2) as substrate and stannous chloride to terminate the reaction and convert all unreacted unstable PGH(2) to PGF(2alpha) before high pressure liquid chromatography analysis. We assessed the induction of PGE synthase in tissues from Harlan Sprague-Dawley rats after LPS-induced pyresis in vivo. Rat PGE synthase was up-regulated at the mRNA level in lung, colon, brain, heart, testis, spleen, and seminal vesicles. Cyclooxygenase (COX)-2 and interleukin 1beta were also up-regulated in these tissues, although to different extents than PGE synthase. PGE synthase and COX-2 were also up-regulated to the greatest extent in a rat model of adjuvant-induced arthritis. The RNA induction of PGE synthase in lung and the adjuvant-treated paw correlated with a 3.8- and 16-fold induction of protein seen in these tissues by immunoblot analysis. Because PGE synthase is a member of the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family, of which leukotriene (LT) C(4) synthase and 5-lipoxygenase-activating protein are also members, we tested the effect of LTC(4) and the 5-lipoxygenase-activating protein inhibitor MK-886 on PGE synthase activity. LTC(4) and MK-886 were found to inhibit the activity with IC(50) values of 1.2 and 3.2 microm, respectively. The results demonstrate that PGE synthase is up-regulated in vivo after LPS or adjuvant administration and suggest that this is a key enzyme involved in the formation of PGE(2) in COX-2-mediated inflammatory and pyretic responses.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2001
                April 2002
                19 April 2002
                : 9
                : 5
                : 263-275
                Affiliations
                Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tenn., USA
                Article
                54289 Neuroimmunomodulation 2001;9:263–275
                10.1159/000054289
                11964521
                d0cf5782-9dc1-4a7c-a022-5612449b6233
                © 2002 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 7, References: 55, Pages: 13
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Cyclooxygenase,SC-560,Prostaglandin E2 ,Fever,Nimesulide,Indomethacin,Antipyretics,Lipopolysaccharide

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