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Melatonin is a product of the pineal gland, where it is ...

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17 Pages
English

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Melatonin is a product of the pineal gland, where it is ...

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The FASEB Journal  express article10.1096/fj.02-0504fje. Published online March 28 , 2003. Prevention of apoptotic and necrotic cell death, caspase-3 activation, and renal dysfunction by melatonin after ischemia/reperfusion Oxana R. Kunduzova,* Ghislaine Escourrou, Marie-Helene Seguelas,* Philippe Delagrange,  France De La Farge, Claudie Cambon,*  and Angelo Parini* *INSERM U388, IFR31, Institut Louis Bugnard, CHU Rangueil, Toulouse 31403 Cedex 4, France; Department of Pathology, CHU Rangueil, Toulouse 31403 Cedex 4, France; Institut de Recherches Internationales Servier, 6, place des Pleiades, 92415 Courbevoie, France; Laboratory of Biochemistry, CHU Rangueil, Toulouse 31403 Cedex 4, France Corresponding author: Angelo Parini, INSERM U388, Institut Louis Bugnard, CHU Rangueil, Bat. L3, 31403 Toulouse Cedex 4, France. E-mail: parini@toulouse.inserm.fr ABSTRACT The pineal hormone melatonin has been reported to protect tissue from oxidative damage. This study was designed to determine whether melatonin could prevent cell events leading to tissue injury and renal dysfunction after ischemia/reperfusion (I/R). Using an in vivo rat model of I/R, we show a significant increase in kidney malondialdehyde concentrations, reflecting lipid peroxidation, and cell apoptosis measured by TUNEL staining. This apoptotic cell death was associated with an increase in the activity of the proapoptotic factor caspase-3, determined by fluorometric protease activity assay. Histomorphological analysis of ischemic kidneys revealed that the most extensive tubular necrosis occurred at 24 and 48 h after reperfusion, which correlated with peak elevations in blood urea nitrogen and creatinine. Rat pretreatment with melatonin prevented lipid peroxidation, cell apoptosis, and necrosis and blocked caspase-3 activity. The prevention of tissue injury was associated with the improvement of renal function as shown by the decrease in blood urea nitrogen and creatinine concentrations. The demonstration that melatonin prevents postreperfusion apoptotic and necrotic cell death and improves renal function suggests that melatonin may represent a novel therapeutic approach for prevention of I/R injury. Key words: oxidative stress kidney rat acute renal failure hormone  A ccmuootmer brmiedoninta ylc  lfiaaninildcu arle m eionnrttditaulyci teoydc  cabuymr sio sdncughr iepnmagit iace/arnretdspi eoirpfnu ulstimhoeon n i(anIr/tyeR n)b syiinvpjeau srscy a( r2ree) , mkuainidintns e (ay1  )t.mr aaInjnosdrp elcaeandut, asteti hooinsf    (3), aortic bypass surgery (4), accidental trauma (5), sepsis (6), hydronephrosis (7), and elective urological operations (8). Although the exact mechanisms involved in the pathogenesis of acute renal failure have not been fully elucidated, it is generally believed that reactive oxygen species (ROS) are key mediators of the I/R-induced damage to the kidney. The excessive formation of ROS causes lipid peroxidation of cell membranes (9, 10), protein and enzyme oxidation (11, 12),