Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats

Among the main factors responsible for perinatal brain injury, inflammation, hypoxia-ischemia and formation of free radicals (FR) appear to play key roles. Melatonin, an endogenously produced indoleamine formed in higher amounts in adults than in neonates, is a potent FR scavenger as well as an indirect antioxidant. Herein, we examined whether melatonin provides significant protection against brain damage and its long-term consequences in a neonatal model of hypoxia-ischemia (HI). Seven day-old rats were subjected to permanent legation of the right common carotid artery followed to 2.5 hrs hypoxia 3 hrs later (HI). The neuroprotective effect of melatonin was evaluated 7 days after HI, or when rats reached adulthood, using behavioral and histological analyses. A beneficial effect was observed with 5 mg/kg melatonin administered before HI. The same dose repeated three times reduced further injury. A significant protective effect was found when 15 mg/kg melatonin was given 30 min before HI or when the same dose was given after HI and administration repeated after 24 and 48 hrs. The latter schedule of administration was used to assess the long-term protective effects. Melatonin did not affect growth rate and behavior at adulthood, but significantly improved the behavioral asymmetry and learning deficits induced by HI. Consistently, brain injury was significantly attenuated in the melatonin-treated ischemic group. The present study demonstrates that melatonin administration before or after HI in immature rats has an excellent and long-lasting benefit on ischemic outcomes suggesting that the drug could represent a potentially safe approach to perinatal brain damage in humans.