Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts

Kargman, Stacia; Charleson, S.; Cartwright, Mark E.; Frank, Jürgen; Riendeau, Denis; Mancini, Joseph A.; Evans, Jillian F.; O’Neill, Gary P.

doi:10.1053/gast.1996.v111.pm8690211

Cited by 427 publications

(272 citation statements)

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“…However, COX-2 is also constitutively expressed in human brain in amounts equal to COX-1 (12), and it is the predominant isoform in the spinal cord of the rat (13). Rat stomach tissue microsomes constitutively express about 5% of COX as COX-2 protein (22), and the macula densa of the rat kidney expresses constitutive COX-2 that is up-regulated by salt deprivation (23). We also have found COX-2 mRNA in the spinal cord and in the pawpad skin of control WT mice.…”

Section: Discussionmentioning

confidence: 99%

Nociception in cyclooxygenase isozyme-deficient mice

Ballou

Botting²,

Goorha³

et al. 2000

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

190

107

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Prostaglandins formed by cyclooxygenase-1 (COX-1) or COX-2 produce hyperalgesia in sensory nerve endings. To assess the relative roles of the two enzymes in pain processing, we compared responses of COX-1-or COX-2-deficient homozygous and heterozygous mice with wild-type controls in the hot plate and stretching tests for analgesia. Preliminary observational studies determined that there were no differences in gross parameters of behavior between the different groups. Surprisingly, on the hot plate (55°C), the COX-1-deficient heterozygous groups showed less nociception, because mean reaction time was longer than that for controls. All other groups showed similar reaction times. In the stretching test, there was less nociception in COX-1-null and COX-1-deficient heterozygotes and also, unexpectedly, in female COX-2-deficient heterozygotes, as shown by a decreased number of writhes.

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Section: Discussionmentioning

confidence: 99%

Nociception in cyclooxygenase isozyme-deficient mice

Ballou

Botting²,

Goorha³

et al. 2000

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

190

107

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“…In the normal stomach, only COX-1 is expressed in detectable amounts. 4,5,7 Following chronic endotoxin administration or induction of chronic gastric ulcers, COX-2 expression is pronounced. 5,7 The results of the present study indicate that COX-2 can also be expressed very quickly after administration of aspirin, and possibly other NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

“…Two forms of the cyclo-oxygenase (COX) enzyme have been characterized. The predominant isoform of COX in a normal stomach is COX-1, 4 and its expression can increase in some circumstances. 5 Conversely, COX-2 is not constitutively expressed in most tissues but can be induced by exposure to certain cytokines, mitogens and endotoxin, and is expressed at sites of in¯ammation, including in the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Aspirin causes rapid up‐regulation of cyclo‐oxygenase‐2 expression in the stomach of rats

Davies

Sharkey

Asfaha

et al. 1997

Aliment Pharmacol Ther

125

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Background:Cyclo‐oxygenase‐1 (COX‐1) is believed to produce prostaglandins vital to mucosal defence, whereas cyclo‐oxygenase‐2 (COX‐2) is induced at sites of inflammation. Little is known about the regulation of COX‐2 in the stomach, particularly during the period following mucosal injury. In this study, we examined COX‐1 and COX‐2 expression shortly after administration of NSAIDs or ethanol.Methods:Fasted rats were given aspirin, salicylate, indomethacin or ethanol (20% or 40%) orally. Three hours later the stomach was excised, the severity of damage scored and samples taken for RT‐PCR of COX‐1 and COX‐2 mRNA and immunohistochemistry. Nitric oxide synthase mRNA (iNOS and eNOS) and activity were also measured.Results:Aspirin, indomethacin and the higher concentration of ethanol produced widespread mucosal damage, whereas salicylate and 20% ethanol caused only superficial epithelial damage. Aspirin caused a significant increase in COX‐2 mRNA expression and a marked increase in COX‐2 immunoreactivity, particularly in the superficial mucosa. Expression of COX‐1 (mRNA and protein) was unaffected by aspirin, as were NOS mRNA expression and enzyme activity. Pre‐treatment with prostaglandin E2 prevented the induction of COX‐2 by aspirin. Salicylate and indomethacin caused modest increases in COX‐2 immunoreactivity but no change in COX‐2 mRNA. Neither concentration of ethanol affected COX‐2 mRNA or protein expression, suggesting that this was a specific response to the aspirin, rather than to injury.Conclusions:These results demonstrate a rapid up‐regulation of COX‐2 expression in response to aspirin, possibly representing a compensatory response to inhibition of gastric prostaglandin synthesis.

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“…This was a proof of concept that sparing COX-1 in the GI tract and possibly in platelets translates to a safer GI profile [11]. In fact, COX-1 is constitutively expressed in the stomach and platelets [15], whereas COX-2 does not appear to be expressed or is expressed at very low levels. However, both COX-isozymes are a source of cytoprotective prostanoids [16a].…”

Section: Introductionmentioning

confidence: 87%

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

Biava

Porretta²,

Poce³

et al. 2011

CMC

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Abstract:The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (tNSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.

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Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts

Cited by 427 publications

References 0 publications

Nociception in cyclooxygenase isozyme-deficient mice

Nociception in cyclooxygenase isozyme-deficient mice

Aspirin causes rapid up‐regulation of cyclo‐oxygenase‐2 expression in the stomach of rats

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

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