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PMID: 12967941 Published · ppublish English Comparative Study Journal Article

Role of cannabinoid CB1 receptors and tumor necrosis factor-alpha in the gut and systemic anti-inflammatory activity of SR 141716 (rimonabant) in rodents.

British journal of pharmacology ·Vol. 140 ·No. 1 ·2003-09-00 ·Pages 115-22

Croci T, Landi M, Galzin AM, Marini P

Abstract

(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.

MeSH Terms
Animals Anti-Inflammatory Agents/pharmacology,therapeutic use Dose-Response Relationship, Drug Duodenal Ulcer/chemically induced,metabolism,prevention & control Duodenitis/chemically induced,drug therapy,metabolism Intestine, Small/drug effects,metabolism,pathology Male Mice Mice, Inbred C57BL Mice, Knockout Piperidines/pharmacology,therapeutic use Pyrazoles/pharmacology,therapeutic use Rats Receptor, Cannabinoid, CB1/antagonists & inhibitors,deficiency,physiology Rimonabant Tumor Necrosis Factor-alpha/metabolism,physiology
Chemicals
Anti-Inflammatory Agents Piperidines Pyrazoles Receptor, Cannabinoid, CB1 Tumor Necrosis Factor-alpha Rimonabant
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Croci Tiziano
Research Center Sanofi Midy, Sanofi-Synthelabo S.p.A., Via G.B. Piranesi 38, 20137 Milan, Italy. [email protected]
Landi Marco
Galzin Anne-Marie
Marini Pietro
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0705412
Email
[email protected]
Published
2003-09-00
Epub
2003-00-29
Pages
115-22
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1574010
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0705412 PMC Full Text View journal details
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