Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats

Dogan, M. Devrim; Ataoglu, Haluk; Akarsu, Eyüp S.

doi:10.1016/s0361-9230(01)00739-0

Cited by 26 publications

(30 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contradiction with the present findings are studies by Dogan et al (20) and Zhang et al (90), which reported that SC-236 blocked LPS hypothermia. In the study by Dogan et al (20), such a blockade occurred only when the dose of SC-236 was substantially higher (40 mg/kg) than the doses (1-15 mg/kg) known to selectively block COX-2 in vivo (31,53).…”

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsescontrasting

confidence: 99%

“…In the study by Dogan et al (20), such a blockade occurred only when the dose of SC-236 was substantially higher (40 mg/kg) than the doses (1-15 mg/kg) known to selectively block COX-2 in vivo (31,53). At such a high dose, SC-236 might have inhibited COX-1, or it might have exerted COX-unrelated effects (39).…”

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsesmentioning

confidence: 94%

“…However, studies of the COX isoforms involved in LPS hypothermia have yielded contradictory results. Dogan et al (20) and Akarsu and Mamuk (2) reported a suppression of LPS hypothermia by a preferential (valeryl-salicylate) or selective (SC-560) COX-1 inhibitor in rats, thus suggesting that this response is mediated by COX-1. Zhang et al (90) reported the opposite, hypothermia-enhancing, effect of SC-560 in the rat, thus suggesting that products of COX-1 inhibit LPS hypothermia in the same species.…”

mentioning

confidence: 99%

“…Zhang et al (90) reported the opposite, hypothermia-enhancing, effect of SC-560 in the rat, thus suggesting that products of COX-1 inhibit LPS hypothermia in the same species. Further complicating the picture, Dogan et al (20,21) and Zhang et al (90) found that a preferential (nimesulide) or selective (SC-236) inhibitor of COX-2 attenuated LPS hypothermia in rats, thus suggesting mediation by COX-2.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Steiner

Hunter²,

Phipps³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

DL, Romanovsky AA. Cyclooxygenase-1 or -2-which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regul Integr Comp Physiol 297: R485-R494, 2009. First published June 10, 2009 doi:10.1152/ajpregu.91026.2008.-Systemic inflammation is associated with either fever or hypothermia. Fever, a response to mild systemic inflammation, is mediated by cyclooxygenase (COX)-2 and not by COX-1. However, it is still disputed whether COX-2, COX-1, neither, or both mediate(s) responses to severe systemic inflammation, and, in particular, the hypothermic response. We compared the effects of SC-236 (COX-2 inhibitor) and SC-560 (COX-1 inhibitor) on the deep body temperature (Tb) of rats injected with a lower (10 g/kg iv) or higher (1,000 g/kg iv) dose of LPS at different ambient temperatures (Tas). At a neutral Ta (30°C), the rats responded to LPS with a polyphasic fever (lower dose) or a brief hypothermia followed by fever (higher dose). SC-236 (2.5 mg/kg iv) blocked the fever induced by either LPS dose, whereas SC-560 (5 mg/kg iv) altered neither the febrile response to the lower LPS dose nor the fever component of the response to the higher dose. However, SC-560 blocked the initial hypothermia caused by the higher LPS dose. At a subneutral T a (22°C), the rats responded to LPS with early (70 -90 min, nadir) dose-dependent hypothermia. The hypothermic response to either dose was enhanced by SC-236 but blocked by SC-560. The hypothermic response to the higher LPS dose was associated with a fall in arterial blood pressure. This hypotensive response was attenuated by either SC-236 or SC-560. At the onset of LPS-induced hypothermia and hypotension, the functional activity of the COX-1 pathway (COX-1-mediated PGE2 synthesis ex vivo) increased in the spleen but not liver, lung, kidney, or brain. The expression of splenic COX-1 was unaffected by LPS. We conclude that COX-1, but not COX-2, mediates LPS hypothermia, and that both COX isoforms are required for LPS hypotension. body temperature; thermoregulation; fever; inflammation SO STRONGLY IS SYSTEMIC INFLAMMATION associated with changes in deep body temperature (T b ) that every clinical definition of the systemic inflammatory response syndrome includes a change in T b (11,48). Whereas the majority (ϳ90%) of patients with systemic inflammation have an increased T b , a number of them (ϳ10%) have a lowered T b (6, 17). Thermoregulatory manifestations are also present in animal models of systemic inflammation. In a rat model of systemic inflammation induced by bacterial LPS, the pattern of T b change depends on the ambient temperature (T a ) and the LPS dose. At a neutral or supraneutral T a (warm environment), fever is the prevailing response; the fever is monophasic when the dose of LPS is low (just suprathreshold), but it turns polyphasic as the dose increases (66, 68, 69, 71, 79); a mild hypothermia may precede the polyphasic fever when the dose of LPS is high (68). At a subneutral T a (cool environment), hypothermia followed by fever is the predominant response; th...

show abstract

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsescontrasting

confidence: 99%

Section: Effects Of Cox-1 and Cox-2 Inhibitors On Lps-induced Responsesmentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Steiner

Hunter²,

Phipps³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…With regard to pyresis, COX-2 but not COX-1 knockout mice demonstrate reduction in LPS-and interleukin-1-induced fevers (24,25), and some new COX-1-selective inhibitors, such as SC-560, have proven ineffective at inhibiting LPS-induced fever in animal models (26,27). Clinically, rofecoxib, a COX-2-selective inhibitor, inhibits naturally occurring fever (28) and also inhibits the maintenance of fever in animal models.…”

Section: Discussionmentioning

confidence: 99%

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression

Chandrasekharan

Dai

Roos

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

1,671

1,111

View full text Add to dashboard Cite

Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an Ϸ5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30 -34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.A cetaminophen is often categorized as a nonsteroidal antiinflammatory drug (NSAID), even though in clinical practice and in animal models it possesses little antiinflammatory activity (1). Like NSAIDs, however, acetaminophen inhibits pain and fever and is one of the world's most popular analgesic/ antipyretic drugs. Despite acetaminophen's long use and popularity it lacks a clear mechanism of action. Flower and Vane showed that acetaminophen inhibited cyclooxygenase (COX) activity in dog brain homogenates more than in homogenates from spleen (2). This gave rise to the concept that variants of COX enzymes exist that are differentially sensitive to this drug and that acetaminophen acts centrally. Yet, even though two isozymes of COX are known, neither isozyme is sensitive to acetaminophen at therapeutic concentrations of the drug in whole cells or homogenates. Instead, COX-1 and -2 in homogenates frequently exhibit the paradoxical property of being stimulated by submillimolar concentrations of acetaminophen and inhibited by supermillimolar levels of the drug (1). This finding suggests that neither isozyme is a good candidate for the site of action of acetaminophen.In analyzing COX-1 and -2 RNA expression in dog tissues, our laboratory observed that the cerebral cortex of dog brain contains two distinct RNAs that hybridized to a canine COX-1 cDNA. ...

show abstract

Specific roles of cyclooxygenase‐1 and cyclooxygenase‐2 in lipopolysaccharide‐induced fever and fos expression in rat brain

Zhang

Lü

Elmquist

et al. 2003

J of Comparative Neurology

View full text Add to dashboard Cite

Fever is a coordinated autonomic, endocrine, and behavioral response mediated by the brain in reaction to inflammatory stimuli. An essential step in transmitting the immune signal to the brain is the formation of prostaglandin E2. Cyclooxygenase (COX) is the critical enzyme in the synthesis of prostaglandins and COX-2, the inducible form of the enzyme, is markedly induced in cells associated with the cerebral blood vessels and the leptomeninges by immune stimuli such as intravenous administration of lipopolysaccharide (LPS). However, the specific roles of COX-1, the constitutive form of cyclooxygenase, and COX-2 in LPS-induced fever are not well understood. We injected LPS i.v. in combination with either a highly selective COX-1 (SC-560) or COX-2 (SC-236) inhibitor to determine the effects of each drug on the subsequent fever response and on the pattern of expression of Fos protein in the brain. The COX-2 inhibitor blocked LPS-induced fever and Fos expression in sites such as the ventromedial preoptic nucleus (VMPO) and the hypothalamic paraventricular nucleus (PVH), although Fos-immunoreactivity in the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and parabrachial nucleus (PB) remained. In contrast, the COX-1 inhibitor resulted in a profound hypothermic response to LPS and blocked LPS-induced Fos-immunoreactivity in the PVH, PB, NTS, and VLM, although it had no effect on the VMPO. Although COX-2 plays a dominant role in mediating fever responses to i.v. LPS, at least some components of the response, including avoiding hypothermia and the induction of Fos in the NTS, VLM, PB, and PVH, appear to depend on COX-1. J.

show abstract

Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats

Cited by 26 publications

References 32 publications

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression

Specific roles of cyclooxygenase‐1 and cyclooxygenase‐2 in lipopolysaccharide‐induced fever and fos expression in rat brain

Contact Info

Product

Resources

About