Melatonin precursor; L-tryptophan protects the pancreas from development of acute pancreatitis through the central site of action

J Physiol Pharmacol. 2004 Mar;55(1 Pt 2):239-54.


Melatonin, produced from L-tryptophan, protects the pancreas against acute damage by improving the antioxidative status of tissue. Melatonin receptors have been detected in the brain, but the contribution of these receptors to the pancreatic protection is unknown. The aim of our study was to compare the effects of melatonin precursor; L-tryptophan given intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on the course of acute pancreatitis. Acute pancreatitis was induced by subcutaneous infusion of caerulein (5 microg/kg-h x 5 h). L-tryptophan was given i.p. (2.5, 25 or 250 mg/kg) or administered into right cerebral ventricle (0.02, 0.2 or 2.0 mg/rat) 30 min prior to the start of caerulein infusion. Plasma amylase, lipase and TNF alpha activities were measured to determine the severity of caerulein-induced pancreatitis (CIP). The lipid peroxidation products: malonylodialdehyde and 4-hydroksynonenal (MDA + 4-HNE) and activity of superoxide dismutase (SOD) were measured in the pancreas of intact or CIP rats with or without L-tryptophan pretreatment. Melatonin blood level was measured by RIA. CIP was confirmed by histological examination and manifested as an edema and rises of plasma levels of amylase, lipase and TNF alpha (by 550%, 1000% and 600%). MDA + 4-HNE was increased by 600%, whereas SOD activity was reduced by 75% in the pancreas of CIP rats. All manifestations of CIP were significantly reduced by pretreatment of the rats with L-tryptophan given i.c.v. at doses of 0.2 or 2.0 mg/rat, or by peripheral administration of this amino acid used at dose of 250 mg/kg i.p. In control rats plasma level of melatonin averaged about 40 +/- 2 pg/ml and was not significantly affected by CIP, by central application of L-tryptophan (0.02, 0.2 or 2.0 mg/rat) or by peripheral administration of this melatonin precursor used at doses of 2.5 or 25 mg/kg i.p. Plasma melatonin level was markedly increased by pretreatment of the rats with L-tryptophan given i.p. at dose of 250 mg/kg. We conclude that central administration of melatonin precursor; L-tryptophan, as well as peripheral application of high dose of this melatonin precursor prevented the pancreatic damage produced by CIP. The favorable effect of peripherally administered L-tryptophan could be related to the rise of melatonin plasma level and to pancreatoprotective action of this indoleamine. The beneficial effect of centrally administered L-tryptophan could be mediated through activation of central receptors for locally produced melatonin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Aldehydes / antagonists & inhibitors
  • Aldehydes / chemistry
  • Amylases / blood
  • Animals
  • Ceruletide / administration & dosage
  • Ceruletide / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Infusions, Parenteral
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Lipase / blood
  • Male
  • Malondialdehyde / antagonists & inhibitors
  • Malondialdehyde / chemistry
  • Melatonin / administration & dosage
  • Melatonin / metabolism*
  • Organ Size / drug effects
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Pancreas / ultrastructure
  • Pancreatitis / chemically induced
  • Pancreatitis / prevention & control*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / antagonists & inhibitors
  • Superoxide Dismutase / chemistry
  • Tryptophan / metabolism
  • Tryptophan / pharmacology
  • Tryptophan / therapeutic use*
  • Tumor Necrosis Factor-alpha / metabolism


  • Aldehydes
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Malondialdehyde
  • Ceruletide
  • Tryptophan
  • Superoxide Dismutase
  • Lipase
  • Amylases
  • Melatonin
  • 4-hydroxy-2-nonenal