Melatonin reduces pancreatic prostaglandins production and protects against caerulein‐induced pancreatitis in rats

Abstract

Melatonin has been used to treat experimental pancreatitis, although not all the drug's therapeutic mechanisms of melatonin have been defined. Prostaglandins (PGs) are proinflammatory mediators that exert their effects mainly locally during inflammatory diseases. The present study was undertaken to examine whether treatment with melatonin influences local PG production. An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuously infusing caerulein (15 mg/kg/hr). Mean arterial pressure and pancreatic perfusion were monitored continuously. Melatonin was delivered via the intraperitoneal route at doses of either 2 or 10 mg/kg, 30 min after caerulein injection. Malondialdehyde and glutathione levels of the pancreas and liver and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hr after infusion of caerulein). Intraperitoneal injection of melatonin (2 and 10 mg/kg) reduced the reduction in systemic arterial pressure and decreased pancreatic perfusion in the rat model of caerulein pancreatitis. Moreover, melatonin treatment changed local PG production toward control level. Higher dose of melatonin was somewhat more effective in preventing the caerulein-induced alterations than was the lower dose.

Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis

“…Previous experimental studies have shown that pretreatment with melatonin could prevent pancreatic inflammation and radically reduce pancreatic tissue damage in rats subjected to acute pancreatitis in different experimental models [13,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73]. This was evidenced by histological assessment of pancreatic tissue and prominent decline of the inflammatory markers, such as edema, neutrophil infiltration, and vacuolization of the acinar cells [60,61,62,63,73].…”

“…This was evidenced by histological assessment of pancreatic tissue and prominent decline of the inflammatory markers, such as edema, neutrophil infiltration, and vacuolization of the acinar cells [60,61,62,63,73]. In animals with acute pancreatitis pretreated with melatonin, there was a significant reduction in the plasma morphometric indicators of pancreatic inflammation severity, blood levels of the enzymes, amylase and lipase, and blood levels of pro-inflammatory cytokines (e.g., TNFα, IL-1β, and IL-6), whereas anti-inflammatory interleukins IL-10 and IL-4 were increased [10,59,62,63,64,65,66,67,68,69,70]. The antioxidant effect of melatonin was expressed as a reduction of lipid peroxidation products (MDA + 4-HNE) in the pancreas and was accompanied by increased activity of antioxidant enzymes SOD, CAT, GPx, and GSH [62,63,64,65,66,67,69,70].…”

“…In animals with acute pancreatitis pretreated with melatonin, there was a significant reduction in the plasma morphometric indicators of pancreatic inflammation severity, blood levels of the enzymes, amylase and lipase, and blood levels of pro-inflammatory cytokines (e.g., TNFα, IL-1β, and IL-6), whereas anti-inflammatory interleukins IL-10 and IL-4 were increased [10,59,62,63,64,65,66,67,68,69,70]. The antioxidant effect of melatonin was expressed as a reduction of lipid peroxidation products (MDA + 4-HNE) in the pancreas and was accompanied by increased activity of antioxidant enzymes SOD, CAT, GPx, and GSH [62,63,64,65,66,67,69,70]. Other mechanisms of the protective action of melatonin on acute pancreatitis involve the improvement of pancreatic blood flow, the reduction of prostaglandin generation, a decrease in myeloperoxidase (MPO), the moderation of apoptosis and necrosis processes in the pancreatic tissue, and synthesis of heat shock proteins [63,66,69,72,74].…”

“…The antioxidant effect of melatonin was expressed as a reduction of lipid peroxidation products (MDA + 4-HNE) in the pancreas and was accompanied by increased activity of antioxidant enzymes SOD, CAT, GPx, and GSH [62,63,64,65,66,67,69,70]. Other mechanisms of the protective action of melatonin on acute pancreatitis involve the improvement of pancreatic blood flow, the reduction of prostaglandin generation, a decrease in myeloperoxidase (MPO), the moderation of apoptosis and necrosis processes in the pancreatic tissue, and synthesis of heat shock proteins [63,66,69,72,74]. Moreover, melatonin has been shown to protect against lung injury and to save gut barrier integrity to reduce bacterial translocation and to prevent sepsis and MODS in acute pancreatitis [75,76].…”

Pinealectomy aggravates acute pancreatitis in the rat

“…Melatonin exerts its beneficial effects through several mechanisms, including scavenging free radicals, activating antioxidative enzymes, inhibiting neutrophil infiltration, promoting neutrophil apoptosis, modulating cytokine production and altering the generation of pancreatic prostaglandins [10,11,18,22,30,46,50]. In addition, the melatonin precursor, L-tryptophan, increases the level of melatonin in the blood and attenuates AP in rats [22,26,50].…”