Protective effects of melatonin as an antioxidant and immunomodulator inburn injury of rats

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Protective effects of melatonin as an antioxidant and immunomodulator inburn injury of rats

 

Author: Han, Xiaohua
Title: Protective effects of melatonin as an antioxidant and immunomodulator inburn injury of rats
Degree: Ph.D.
Year: 2003
Subject: Hong Kong Polytechnic University -- Dissertations
Melatonin -- Physiological effect
Antioxidants -- Physiological effect
Immunological adjuvants
Burns and scalds -- Treatment
Department: School of Nursing
Pages: xix, 135 leaves : ill. (some col.) ; 30 cm
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b1733042
URI: http://theses.lib.polyu.edu.hk/handle/200/3979
Abstract: Multiple organ dysfunction or failure (MOD, MOF) and serious infection are the main complications in major burn and account for most of the deaths in severely burned patients. Major burn may induce obvious oxidative damages in remote organs, which are closely associated with MOD occurring at the early stage of burn. Furthermore, major burn also predominantly impairs the cell-mediated immunity (CMI), leading to increased susceptibility to infections. The present study aims to investigate the putative protective effects of melatonin, a very potent antioxidant and immunomodulator proved in many other animal models, on MOD and depressed CMI using a 30% total body surface area (TBSA) rat burn model. The results were as followed: (1) The first study was carried out in 30 male Sprague-Dawley rats to observe the changes of haematocrit, plasma total protein (TP) concentrations and plasma malondialdehyde (MDA) levels at 6 h postburn. The significantly increased haematocrit and decreased TP concentrations indicated the existence of hemoconcentration and hypoproteinemia following the 30% TBSA burn, Melatonin treatment (10 mg/kg, given i.p. immediately postburn) was found to reduce the increased plasma levels of MDA as well as the formation of tissue oedema in the lung and burned skin. These results suggested that melatonin might act as an antioxidant and exert some beneficial effects on bum-induced tissue damages. (2) The protective effects of melatonin on oxidative stress in burn injury were further investigated in four remote organs (liver, kidney, lung and heart) at 6 h, 24 h and 72 h postburn by measuring the tissue levels of MDA and reduced glutathione (GSH). It was found that oxidative stress was evident within 24 h postburn in all tested organs, as evidenced by increased MDA levels and decreased GSH levels. In the kidney, the oxidative damages lasted up to 72 h following burn. The treatment with a single dose of melatonin (10 mg /kg, i.p.) significantly inhibited these alterations at 6 h postburn. However, repeated administrations of melatonin (10 mg/kg each time, given i.p. immediately postburn and then every 12 hours until 24 h and 72 h postburn) did not exert similar effect as the single injection. To further explore the mechanisms responsible for the protective effect of melatonin, activities of three enzymes (glutathione peroxidase: GSH-Px; superoxide dismutase: SOD; myeloperoxidase: MPO), all of which are involved in burn-induced oxidative stress, were measured at 6 h postburn. GSH-Px and SOD (two main antioxidant enzymes) showed different responses to bum injury. The activities of GSH-Px were significantly decreased in all tested organs following bum, while SOD activities showed an increase in the kidney and the lung. Melatonin treatment (10 mg /kg, one dose) stimulated the liver GSH-Px and SOD activities, but had no significant effect in other three organs. In addition, MPO (an indicator for neutrophil infiltration) was found to increase markedly in all remote organs after burn. This implies that neutrophils are the very important source for the generation of free radicals. Increased MPO levels were partially alleviated by melatonin treatment. In summary, melatonin may protect the vital organs against oxidative damages in burn injury. The antioxidant action of melatonin depends predominantly on its high free radical scavenging capacity, and in the liver, the antioxidant action is also enhanced by the stimulation of melatonin on GSH-Px and SOD activities. Melatonin therapy also decreases the neutrophil infiltration, thus preventing the neutrophil-mediated tissue damage in burn injury. (3) The protective effect of melatonin on MOD was also assessed at 6 h, 24 h and 72 h postburn by measuring the serum levels of organ-specific markers (ALT, AST and ALP for liver dysfunction; creatinine and urea for kidney dysfunction; CK and LDH for heart dysfunction). The rises in these biomedical markers occurred as early as 6 h postburn and lasted up to 24 h postburn before the complete restoration at 72 h postburn. A single dose of melatonin exerted a significant protection against liver, kidney and heart dysfunction. Unfortunately, repeated administrations of melatonin had no effects. This failure is most likely due to the long injection interval (every 12 hours) relative to the very short half-life of melatonin. (4) The improvement of melatonin on the depressed cellular immune response was also investigated in the present study. Severe immunosuppression was observed at Day 7 postburn, as evidenced by the significant inhibition in the ear swelling during the contact hypersensitivity reaction (CHR). Melatonin treatment (10 mg/kg, i.p. daily for 7 days) markedly enchanced the CHR but did not restore it completely. This result suggested another beneficial effect of melatonin as an immuno-enhancing agent in bum injury. In conclusion, melatonin may exhibit significant protections against burn-induced MOD and immunosuppression, acting as a very effective antioxidant and immunomodulator. These beneficial effects together with the very low toxicity may enable melatonin to become a promising therapeutic agent of clinical significance in burn injuries.

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