Surg Today (2005) 35:744–750 DOI 10.1007/s00595-005-3027-2 Protective Effect of Melatonin Against Ischemia/Reperfusion-Induced Oxidative Remote Organ Injury in the Rat Ayhan Kaçmaz 1 , E. Yilmaz User 1 , A. Özer S ¸ ehirli 2 , Metin Tilki 1 , Sirri Ozkan 1 , and Göksel S ¸ ener 2 1 Third Department of Surgery, Haydarpas ¸a Numune Hospital, Istanbul, Turkey 2 Department of Pharmacology, School of Pharmacy, Marmara University, Tıbbiye Cad., 34668 Istanbul, Turkey Key words Melatonin · Ischemia/reperfusion · Lipid peroxidation · Glutathione · Myeloperoxidase Introduction The re-establishment of the blood flow to ischemic tis- sue is the therapeutic goal in the treatment of arterial occlusion. However, surgically restoring the blood flow often leads to continued or accelerated local tissue in- jury and systemic toxicity, as first described in 1960. 1 Practically all surgical procedures involve a period of ischemia followed by reperfusion. In addition, some diseases such as shock, sepsis, and pancreatitis, which surgeons frequently have to deal with, also all have ischemia and reperfusion periods. As a result, all types of surgery can benefit from the prevention and/or improved management of the tissue injury associated with reperfusion. The mechanisms underlying ischemia/ reperfusion (I/R)-induced organ damage are likely mul- tifactorial and interdependent, involving hypoxia, in- flammatory responses, and free radical damage. 2,3 Reoxygenation of the ischemic tissue may promote the generation of various reactive oxygen species (ROS), endothelial cells, and complement activation, which are known to have deleterious effects on various cellular functions. 4,5 The organ dysfunction that accom- panies this condition is generally associated with in- creased microvascular permeability, interstitial edema, impaired vasoregulation, inflammatory cell infiltration, and parenchyimal cell dysfunction and necrosis. 6 Ischemia/reperfusion elicits an acute inflammatory response characterized by activation of neutrophils. Activated neutrophils are known to induce tissue injury through the production and release of reactive oxygen metabolites and cytotoxic proteins (e.g., proteases, myeloperoxidase, lactoferrin) into extracellular fluid. 7 The inflammatory mediators released as a consequence Abstract Purpose. Oxygen free radicals are considered to be im- portant components involved in the pathophysiological tissue alterations observed during ischemia/reperfusion (I/R). Based on the potent antioxidant effects of mela- tonin, we investigated the putative protective role of melatonin against I/R-induced oxidative remote organ injury. Methods. Wistar albino rats were subjected to 1 h of infrarenal aortic occlusion followed by 1 h of reper- fusion to induce I/R damage. Melatonin (10 mg/kg, s.c.) or vehicle was administered twice, 15 min prior to ischemia and immediately before the reperfusion period (I/R + Mel or I/R groups). At the end of the reperfusion periods, the rats were decapitated and hepatic, ileal, and lung tissue samples were removed for biochemical analyses of: malondialdehyde (MDA), an end product of lipid peroxidation; the glutathione (GSH) levels, a key antioxidant; and the myelo- peroxidase (MPO) activity, as an indirect index of neutrophil infiltration. The serum aspartate amino- transferase (AST) and alanine aminotransferase (ALT) levels were measured to evaluate the liver function. The wet/dry lung weight ratio was calculated to determine the extent of lung damage. Results. The results revealed the occurrence of I/R- induced oxidative organ damage, as evidenced by in- creases in the MDA and MPO activity, and a decrease in GSH. Furthermore the AST, ALT levels, and the wet/dry lung weight ratio, which all increased due to I/R, were all observed to decrease after melationin treatment. Conclusion. Since melatonin administration reversed these oxidant responses, it seems likely that melationin has a protective effect against oxidative organ damage induced by I/R. Reprint requests to: G. S ¸ ener Received: April 14, 2003 / Accepted: January 18, 2005