title: Autophagy in hypoxia-ischemia induced brain injury.
abstract: Autophagy is an endogenous tightly regulated process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates. Emerging data indicate a strong and complex interaction among autophagy, apoptosis and necrosis. We studied these interactions in a neonatal model of hypoxia-ischemia (HI). Autophagy was assessed by evaluating the expression of the two autophagy proteins beclin 1 and LC3, and by "in vivo" autophagic vesicles formation and clearance using monodansylcadaverine (MDC). Both autophagy and apoptosis pathways were increased in the same neurons at short times after HI. Neuroprotective drugs also increased autophagy. Interestingly, pharmacological inhibition of autophagy switched cell death phenotypes from apoptosis to necrosis. Rapamycin, that enhances autophagy by inhibition of mTOR and previously shown to be neuroprotective in our animal model of HI when administered before the ischemic insult, was used to study the potential interaction between autophagy and survival pathways. Rapamycin, besides inducing autophagy, also increased Akt and CREB (cAMP response element-binding protein) phosphorylation in the same cells. The pharmacological inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt axis reduced the neuroprotective effect of rapamycin without affecting autophagy. Conversely, pharmacological inhibition of autophagy reduced the neuroprotective effect of rapamycin without affecting Akt phosphorylation. Both treatments, however, caused a rapid switch towards necrotic cell death. Thus, autophagy can be part of an integrated pro-survival signalling which includes the PI3K-Akt- mTOR axis and its activation seems be crucial for pharmacological and ischemic preconditioning.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy. walter.balduini@uniurb.it
authors.forename: Walter
authors.initials: W
authors.lastname: Balduini
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Buonocore
mesh_terms: D001343:Autophagy; D001930:Brain Injuries / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000503:physiopathology*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000209:etiology / Q000503:physiopathology