Cell death and survival are critical events for neurodegeneration, mitochondria being increasingly seen as important determinants of both. Mitochondrial dysfunction is considered a major causative factor in Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity and NO production, and disrupted electron transport system and mitochondrial permeability transition, have all been involved in impaired mitochondrial function. Melatonin, the major secretory product of the pineal gland, is an antioxidant and an effective protector of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective to prevent oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of AD, PD and HD. These effects are seen at doses 2-3 orders of magnitude higher than those required to affect sleep and circadian rhythms, both conspicuous targets of melatonin action. Melatonin is selectively taken up by mitochondria, a function not shared by other antioxidants. A limited number of clinical studies indicate that melatonin can improve sleep and circadian rhythm disruption in PD and AD patients. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100mg/day are needed to assess its therapeutic validity in neurodegenerative disorders.

Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. Androgen excess alters liver lipid metabolism

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To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases.