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We have previously shown that in neonatal rats subjected to hypoxia-ischemia (HI) rapamycin administration increases autophagy, decreases apoptosis and significantly reduces brain damage. After HI, when autophagy is blocked neuronal cells rapidly progress toward necrotic cell death. The present study was undertaken to assess the potential role of activation of autophagic and phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathways in the neuroprotective effect of rapamycin. Rapamycin administration caused a significant reduction of 70 kDa s6 kinase (p70S6K) phosphorylation and a significant increase of the autophagic proteins Beclin 1 and microtubule-associated protein 1 light chain 3 (Lc3), as of monodansylcadaverine (MDC) labeling in the lesioned side. The phosphorylation of Akt and cAMP response element binding protein (CREB) was increased in neuronal cells, and both p-Akt and p-CREB colocalized with Beclin 1. Wortmannin (WM) administration significantly reduced Akt and CREB phosphorylation as well as the neuroprotective effect of rapamycin but did not affect the phosphorylation of p70S6K, the expression of Beclin 1 and LC3, and MDC labeling. In contrast, 3-methyladenine (3MA) reduced the increased Beclin 1 expression, the MDC labeling and the neuroprotective effect of rapamycin without affecting Akt phosphorylation. However, both compounds significantly increased necrotic cell death. Taken together, these data indicate that in neonatal HI autophagy can be part of an integrated prosurvival signaling which includes the PI3K-Akt-mammalian target of rapamycin (mTOR) axis. When the autophagic or the PI3K-Akt-mTOR pathways are interrupted cells undergo necrotic cell death. © 2010 Landes Bioscience

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.