Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces chronic colonic inflammation in rats.
Recent studies have shown the implication of the peroxisome proliferator-activated receptor gamma (PPARgamma) in control of inflammation, immune and apoptotic responses during early experimental colitis. However, there is little information about the effects of these agents on colonic mucosa under chronic inflammatory conditions. In this study, we have evaluated the effects of rosiglitazone, a PPAR-gamma agonist, on the chronic injury caused by intra-colonic administration of trinitrobenzensulfonic acid (TNBS) in rats. Rosiglitazone (1 and 5mg/kg p.o.) was administered by oral gavage, 24h after TNBS instillation and daily during 2 weeks before killing the rats. Colons were removed for histological and biochemical analysis. Administration of rosiglitazone corrected the disorders in morphology associated to lesions, significantly reduced the ulceration index, the rise of myeloperoxidase (MPO) and the levels of tumour necrosis factor alpha (TNF-alpha). In addition, rosiglitazone treatment increased prostaglandin (PG)E(2) production and returned PGD(2) to basal levels. Also, reduced cyclooxygenase (COX)-2 and nuclear transcription factor NF-kappa B (NF-kappaB) p65 proteins expression. Furthermore, treatment of rats with rosiglitazone caused a significant increase of TNBS-induced apoptosis. In summary, rosiglitazone exerts protective effects in chronic experimental colitis. The anti-inflammatory effects seem to be related to impairment of neutrophil function, absence of up-regulation of TNF-alpha and decrease of nuclear NF-kappaB p65 expression. Our results also suggest that the activation of the PPARgamma pathway reduces COX-2 overexpression, returns the increased PGD(2) values to basal levels and induces a significant increase of TNBS-induced apoptosis. We conclude that rosiglitazone represents a novel approach to the treatment of ulcerative colitis.
Sánchez-Hidalgo
M
M
Department of Pharmacology, Faculty of Pharmacy, University of Sevilla, Profesor García González Street 2, 41012 Seville, Spain.
Martín
A R
AR
Villegas
I
I
Alarcón De La Lastra
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
D008565:Membrane Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat