The present study was carried out to investigate the effect of two antioxidant drugs namely melatonin and N-acetylcysteine on two experimental models of free radical mediated pathological conditions. The first one is acetaminophen induced acute hepato and renal toxicity in mice. The second one is fructose induced metabolic syndrome in rats.
The first part of this work was devoted to investigate the effect of prophylactic intraperitoneal administration of melatonin (10mg/kg) or N- acetylcysteine (150mg/kg) either singly or in combination 30 minutes before induction of the acetaminophen toxicity by single intraperitoneal dose of acetaminophen on some liver function tests namely serum activity of alanine & aspartate transaminases, renal function tests namely serum concentration of urea and creatinine, parameters of oxidative stress namely concentrations of malondialdehyde and reduced glutathione in hepatic & renal tissue homogenate in mice and histopathological study using H&E sections after 4 and 24 hours of induction of hepato-renal toxicity by acetaminophen.
The results of this part of the work revealed that acetaminophen administration produced profound deterioration of hepatic and renal functions. The former was maximally manifested after 4 hours as elevation of serum concentration of alanine and aspartate transaminases. The histopathological examination showed areas of hemorrhage, leukocytic infiltration and hepatic cell degeneration. The latter was maximally manifested after 24 hours of acetaminophen administration as significant elevation of serum urea and creatinine concentration, tubular degeneration and interstitial inflammation. This was associated with a state of oxidative stress manifested as elevation of malondialdehyde and depression of reduced glutathione concentrations in hepatic and renal tissue homogenates. The discrepancy in appearance of hepatic and renal toxicity is due to time dependent distribution of acetaminophen which is first accumulated in liver then passed to the kidney for excretion.
Administration of either drugs either singly or in combination partially ameliorated acetaminophen hepato-renal toxicity .This was strongly correlated with improving parameters of oxidative stress .This emphasizes the role of oxidative stress in pathogenesis of tested pathological conditions as well as the mechanism of action of melatonin which acted mainly as free radical scavenger then as inducer of key enzymes of glutathione synthesis. On the other hand N-acetylcysteine acted by increase synthesis of glutathione and as anti-inflammatory agent. Co-administration of both drugs proved to be more effective than either of them due to difference in their mechanism of action.
In the second part of this work, administration of fructose in drinking water to rats for 8 weeks produced a condition similar to metabolic syndrome in the form of systolic and diastolic hypertension, fasting hyperglycemia and hyperinsulinemia, elevation of HOMA-IR ratio, marked increase in serum concentrations of total cholesterol, LDL cholesterol, triglycerides and reduction of HDL cholesterol concentrations. This was associated with a state of oxidative stress manifested by elevation pancreatic tissue homogenates concentration of malondialdehyde and reduction of that of glutathione. This was attributed to fructose mediated increase in generation of free radicals through increase urate metabolism mediated by increase ATP catabolism. This may cause dysfunction of endothelial cells, B islet cells and insulin receptors.
Pretreatment with either melatonin (25ug/ml/day) or N-acetylcysteine (2g/kg/day) partially reversed fructose induced metabolic syndrome through their common mechanism of as antioxidants. Melatonin acts mainly as free radical scavenger and N-acetylcysteine as glutathione regenerator. Melatonin was more effective in decreasing the systolic hypertension due to central GABA mediated antihypertensive effect as well as peripheral angiotensin II antagonistic and nitric oxide promoting effect. In all other metabolic parameters of metabolic syndrome there were insignificant differences between the two tested drugs. These findings suggest that the antioxidant therapy may represent a new helpful pharmacologic approach against insulin resistance and type-2 diabetes.
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