Nesfatin-1 protects from acute pancreatitis: role of melanocortin receptors.

Nesfatin-1, a recently discovered peptide, was shown to have anti-inflammatory effects. Acute pancreatitis (AP) is a life-threatening condition caused by various reasons. Although the etiology of AP is well-known, its pathogenesis is not clear. The aim of this study is to investigate the possible anti-inflammatory role of nesfatin-1 and its probable protective underlying mechanisms in an acute pancreatitis model. Caerulein was applied intraperitoneally to induce acute pancreatitis in Sprague-Dawley female rats. Nesfatin-1 was administered 5 minutes before the application of caerulein to determine its potential anti-inflammatory role on AP. Five minutes before nesfatin-1 injection, in order to investigate the underlying mechanism, oxytocin receptor antagonist (atosiban), melanocortin receptor antagonist (HS024), or ghrelin receptor antagonist (cortistatin) were administered. Five minutes after nesfatin-1 administration, two doses of caerulein were applied one hour apart. The rats were sacrified 12 hours after the first caerulein dose for serum and pancreatic tissue sampling. Microscopic damage scoring, malondialdehyde and glutathione levels, myeloperoxidase activity, luminol and lucigenin chemiluminescence levels in pancreatic tissue and amylase, lipase, trypsinogen-2 levels in serum were evaluated. Oxidative damage was decreased with nesfatin-1 treatment in the acute pancreatitis model (P < 0.05 - 0.001). The administration of HS024 reversed the effect of nesfatin-1, via increasing lipase, amylase, trypsinogen-2, malondialdehyde (MDA), myeloperoxidase (MPO) and lucigenin levels (P < 0.05 - 0.01). Atosiban pre-treatment elevated MPO activity, luminol and lucigenin chemiluminescence levels (P < 0.01 - 0.001) and cortistatin increased lucigenin and luminol chemiluminescence (P < 0.05 - 0.01). Although receptor antagonists reversed the effect of nesfatin-1 on related biochemical parameters, no significant difference was found in histological scoring. Our results indicated that nesfatin-1 had an anti-inflammatory effect on acute pancreatitis via mainly effecting melanocortin receptors.

The effect of estrogen receptor agonists on pancreaticobiliary duct ligation induced experimental acute pancreatitis.

The 17ß-estradiol plays a role in physiology of pancreas and may protect it from inflammation. To examine the possible anti-inflammatory effects of 17ß-estadiol in pancreaticobiliary duct ligated (PBDL) acute pancreatitis (AP) model, and the underlying mechanism that 17ß-estradiol acts on, via evaluating the direct and the receptor related effects by using 17ß-estradiol, ER-α and -ß agonists. In the study both sexes of rats (n = 88) were used. Animals were divided into two groups as PBDL and PBDL + ovariectomized. ER-α agonist propyl-pyrazole-triol (PPT; 1 mg/kg/day), ER-ß agonist diarylpropionitrile (DPN; 1 mg/kg/day) and 17ß-estradiol (10 mg/kg/day) were administered to the groups for 3 days following AP induction. On the 3rd day, lung and pancreas tissues and serum samples were taken for malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), superoxide dismutase (SOD) and interleukin (IL) assays, and histological analyses. In both tissues of male and female AP groups MPO, MDA, SOD levels were increased (P < 0.05 - 0.01) and GSH levels were decreased (P < 0.05). Pancreas and lung MDA and SOD levels were improved with all treatments in female, except lung MDA levels of PPT-treated ones, while lung MDA and SOD levels were improved by PPT and 17ß-estradiol in females and via PPT in males (P < 0.05 - 0.001). The increased MPO levels were inhibited with PPT in male pancreas and female lung and with 17ß-estradiol in female pancreas (P < 0.05). The increased pro-inflammatory ILs were declined by treatments (P < 0.05 - 0.001). 17ß-estradiol and ER-α and -ß agonists reduced oxidative pancreatic and pulmonary damage. Estrogen and agonists might have protective role in AP.

Anti-inflammatory effects of nesfatin-1 in rats with acetic acid - induced colitis and underlying mechanisms.

Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 µg/5 µl) or vehicle (5 µl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and GHSR-1a administration alleviated the protective effect of nesfatin-1 from microscopic and oxidant damage parameters and lipid peroxidation (P < 0.05 - 0.001). The results of the study suggest that nesfatin-1 had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of nesfatin-1 on colitis might occur via oxytocin and ghrelin receptors.