comparative study of the effect of peroxisome proliferator activated receptor gamma agonist and angiotensin converting enzyme inhibitor on experimental pancreatitis in rats

ABSTRACT

There is accumulating evidence that peroxisome proliferators-activated receptor gamma [PPARgamma] plays important roles in the processes of fat metabolism, adipocyte differentiation, tumorigenesis, inflammation, and a variety of immune processes. Thiazolidinediones [TZDs], including rosiglitazone, are high-affinity ligands for [PPAR-gamma] and are used as insulin-sensitizing drugs. They inhibit chernokines [interleukin-8] in epithelial cells, leading to the suggestion of their use in inflammation. Angiotensin-converting enzyme [ACE] inhibitors are commonly prescribed to reduce the risk of myocardial infarction and cardiovascular death. They also modulate proinflammatory signals and reduce macrophage accumulation. Thus, they may have beneficial action in various inflammatory conditions. The present study aimed to investigate the possible anti-inflammatory effects of [PPAR] gamma agonist [rosiglitazone] and ACE inhibitor [lisinopril] in cerulein-induced chronic pancreatitis [CP] in rats. Also to compare between their actions, separately or in combination, in CP. Fifty male albino rats weighing from 150-200 gm were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group, they were received 1 ml physiological saline [0.9%], by intraperitoneal [i.p.] injections six hourly, three times a week for three weeks. Group II cerulein-induced CP group [40 rats] injected with cerulein i.p. in a dose of 50 microg/kg.b.wt. six hourly, three times a week for three weeks. Rats were further subdivided into A, B, C, and D, each often rats. Group- A received 1ml of 2% gum acacia daily orally for two weeks starting from the third week of cerulein administration. Groups B and C treated with rosiglitazone in a dose of 3 mg/kg.b.wt. or lisinopril in a dose of 2.5 mg/kg.b.wt orally daily for the same previous duration. Group-D, treated with both drugs for the same previous doses and duration. I.p. injection of cerulein produced significant increases in serum levels of amylase, tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF- beta1] with elevations of pancreatic tissue content of hydroxyproline [HPO] and myeloperoxidase [MPO] activity. Rosiglitazone and lisinopril produced improvement of CP manifested by the significant decreases in the previous measured parameters, but rosiglitazone, provided a better effect. Combined administration of rosiglitazone and lisinopril, produced marked and superior ant-inflammatory and antifibrotic actions. I.p. injection of cerulein is a reliable method for induction of CP resembles the human CP. RAS proved to be incriminated in the pathogenesis of CP as evidenced by the effective therapeutic effect of lisinopril in cerulein-induced CP. Rosiglitazone, provided a better effect than lisinopril, reflecting the important role of PPARgamma in CP. The combination of both drugs proved to be superior in alleviated chronic pancreatitis which may be due to the synergistic anti-inflammatory, anti-oxidant and antifibrotic effects of these drugs