Effects of Melatonin on Acute Necrotizing Pancreatitis in Rats

Zusammenfassung

In dieser Studie wurde der Einfluss von Melatonin auf eine nekrotisierende Pankreatitits (ANP) bei Ratten untersucht. Die Entstehung einer ANP führt zu einem signifikanten Anstieg der Mortalität, zu Pankreasnekrosen, zur Zunahme der Serumaktivität von Amylase, Alanin-Aminotransferase (ALT) und Interleukin 6 (IL-6), der Laktatdehydrogenase (LDH) in der bronchoalveolären Lavage (BAL), zum Anstieg der Serumkonzentration von Harnstoff, der Gewebeaktivität der Myeloperoxidase (MPO) und von Malondialdehyd (MDA) im Pankreas und der Lunge sowie zu einem signifikanten Abfall der Serumkonzentration von Kalzium, des Blutdrucks, der Urinausscheidung und der Sauerstoffsättigung. Melatonin inhibiert die Veränderungen des Blutdrucks, der Urinausscheidung, der Sauerstoffsättigung, der Serumkonzentration von Kalzium und Harnstoff, die Gewebeaktivität der MPO und MDA im Pankreas und der Lunge, LDH in der BAL und reduziert teilweise die Serumaktivität von IL-6. Melatonin hat keinen Einfluss auf die Serumaktivität der Amylase, der ALT, auf die Pankreasnekrosen und die Mortalität. Die Anwendung von Melatonin hat nur einen geringen Einfluss auf den Verlauf der Pankreatitis. Jedoch könnte es zur supportiven Therapie während einer akuten nekrotisierenden Pankreatitis nützlich sein.

Abstract

The aim of this study was to investigate the influence of melatonin on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increases in mortality rate, pancreatic necrosis and increased serum activity of amylase, alanine aspartate transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO₂. Melatonin inhibited the changes in blood pressure, urine output, pO₂, serum concentration of urea, and calcium, tissue activity of MPO and MDA in the pancreas and lung, LDH level in BAL fluid, and partially reduced serum activity of IL-6. Melatonin did not change serum activity of amylase, ALT, pancreatic damage and the mortality rate. The use of melatonin has a limited value on the course of ANP. It may be useful as a supportive treatment during ANP.

Schlüsselwörter

Akute Pankreatitis - Melatonin - Antioxidant - freie Radikale

Key words

Acute pancreatitis - melatonin - antioxidant - free radicals

References

• 1 Schwartz M, Thomsen J, Meyer H. et al . Frequency and time course of pancreatic and extra pancreatic bacterial infection in experimental pancreatitis in rats.  Surgery. 2000;  127 427-432
• 2 Steer M L. Etiology and pathophysilogy of acute pancreatitis. Go VLV, Diamagno EP, Gardner JD, Lebenthal E, Reber A, Scheele GA The pancreas: biology, pathophysilogy, and disease New York; Raven Press 1993: 581-592
• 3 Klar E, Messmer K, Warshaw. et al . Pancreatic ischemia in experimental acute pancreatitis: mechanism, significance and therapy.  Br J Surg. 1990;  77 1205-1210
• 4 Alhan E, Kücüktülü U, Ercin C. et al . The effects of dopexamine on acute necrotizing pancreatitis in rats.  Eur J Surg. 2001;  167 761-766
• 5 Norman J. The role of cytokines in the pathogenesis of acute pancreatitis.  Am J Surg. 1998;  1175 76-83
• 6 Alhan E, Cicek R, Erçin C. et al . Effects of the tyrosine kinase inhibitor tyrphostin AG 556 0 n acute pancreatitis in rats.  Eur J Surg. 2002;  68 557-562
• 7 Beger H G, Bittner R, Büchler M. Hemodynamic data pattern in-patients with acute pancreatitis.  Gastroenterology. 1986;  90 74-79
• 8 Rau B, Poch B, Gansauge F. et al . Pathophysiologic role of oxygen free radicals in acute pancreatitis.  Ann Surg. 2000;  31 352-360
• 9 Yamamoto Y. Oxidation of biological membranes and its inhibition. Free radical chain oxidation of erythrocyte ghost membranes by oxygen.  Biochem Biophys acta. 1985;  819 29-36
• 10 Koster J F, Slee R G. Lipid peroxidation of human erythrocyte ghosts induced by organic hydro peroxides.  Biochem Biophys Acta. 1983;  752 233-239
• 11 Farber J L, Kyle M E, Coleman J B. Mechanisms of cell injury by activated oxygen species.  Lab Invest. 1990;  62 670-679
• 12 Tate R M, Morris H G, Schroeder W R. et al . Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lung.  J Clin Invest. 1984;  74 608-613
• 13 Hotter G, Closa D, Prats N. et al . Free radical enhancement promotes leukocytes recruitment through a PAF and LTB4 dependent mechanism.  Free radical Biol Med. 1997;  22 947-954
• 14 Stanfey H, Bulkley G B, Cameron J L. The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis.  Ann Surg. 1984;  200 405-413
• 15 Schoenberg M H, Büchler M, Beger H G. Oxygen radicals in experimental pancreatitis.  Hepato-Gastrenterol. 1994;  41 313-319
• 16 Schulz H U, Niederau C. Oxidative stress-induced changes in pancreatic acinar cells: insight from in vitro studies.  Hepato-Gastrenterol. 1994;  41 309-312
• 17 Schoenberg M H, Birk D, Beger H G. Oxidative stress in acute and chronic pancreatitis.  Am J Clin Nut. 1995;  62 1306S-1314S
• 18 Huether G, Poeggeler B, Reimer A. et al . Effect of tryptophan administration on circulating Melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract.  Life Sci. 1992;  51 945-953
• 19 Vural H, Sabuncu T, Arslan S O. et al . Melatonin inhibits lipid peroxidation and stimulates the antioxidant status of diabetic rats.  J Pineal Res. 2001;  31 193-198
• 20 Qi W Tan DX, Reiter R J, Kim S J. et al . Melatonin reduces lipid per oxidation and tissue edema in cerulein induced acute pancreatitis in rats.  Dig Dis Sci. 1999;  44 2257-2262
• 21 Jaworek J, Bonjo J, Leja-Szps A. et al . Sensory nerves in central and peripheral control of pancreatic integrity by leptin and melatonin.  J Physiol Pharmacol. 2002;  53 51-74
• 22 Jaworek J, Leja-Szps A, Bonjo J. et al . Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein over stimulation or ischemia/reperfusion.  J Pineal Res. 2003;  34 40-52
• 23 Schmidt J, Rattner M D, Lewandrowski K. A better model of acute pancreatitis for evaluating therapy.  Ann Surg. 1992;  215 44-56
• 24 Sookhal S, Wang J J, McCourt M. et al . A novel therapeutic strategy for attenuating neutrophil-mediated lung injury in vivo.  Ann Surg. 2002;  235 283-291
• 25 Lankisch P G, Pohl U, Otto J. et al . When should treatment of acute experimental pancreatitis be started? The early phase of bile-induced acute pancreatitis.  Res Exp Med. 1988;  188 123-129
• 26 Schierwagen C, Bylund-Fellenius A C, Lundberg C. Improved method for quantification of tissue PMN accumulation measured by myeloperoxidase.  J Pharmacol Meth. 1990;  23 179-186
• 27 Lowry O H, Roseburgh N L, Farr A L. Protein measurement with folin phenol reagent.  J Biol Chem. 1951;  193 265-275
• 28 Buege T A, Aust S D. Microsomal lipid peroxidation.  Meth Enzymol. 1978;  52 302-310
• 29 Tan D X, Chen L D, Poeggeler B. et al . Biochemical reactivity of Melatonin with reactive oxygen and nitrogen species: a review of the evidence.  Cell Biochem Biophys. 2001;  34 237-256
• 30 Banks P A, Tenner S, Noordhoek E C. et al . Does pancreatic necrosis predict severity in-patients with acute necrotizing pancreatitis?.  Digestion. 1996;  57 218-223
• 31 Murakami H, Nakao A, Kishimoto W. et al . Detection of O2-generation and neutrophil accumulation in rat lungs after acute necrotizing pancreatitis.  Surgery. 1995;  118 547-554
• 32 Song A M, Bhagat L, Singh V P. et al . Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury.  Am J Physiol Gastrointest Liver Physiol. 2002;  283 G1166-1174
• 33 Nathens A V, Neff M J, Jurkovich G J. et al . Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.  Ann Surg. 2003;  236 814
• 34 Weidenhach H, Lerch M M, Gress T M. et al . Vasoactive mediators and the progression from edematous to necrotizing experimental acute pancreatitis.  Gut. 1995;  37 434-440
• 35 Borgström A, Appelros S, Müller C A. et al . Role of activation peptides from pancreatic proenzymes in the diagnosis and prognosis of acute pancreatitis.  Surgery. 2002;  131 125-128