IGF-1 protects oligodendrocyte progenitors against TNFα-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway

Proinflammatory cytokine-mediated injury to oligodendrocyte progenitor cells (OPCs) has been prosposed as a cause of periventricular leukomalacia (PVL), the most common brain injury found in preterm infants. Preventing death of OPCs is a potential strategy to prevent or treat PVL. In the current study, we utilized an in vitro cell culture system to investigage the effect of insulin-like growth factor-1 (IGF-1) on tumor necrosis factor-alpha (TNF alpha)-induced OPC injury and the possible mechanisms involved. OPCs were isolated from neonatal rat optic nerves and cultured in chemically defined medium (CDM) supplemented with platelet-derived growth factor and basic fibroblast growth factor. Exposure to TNF alpha resulted in death of OPCs. IGF-1 protected OPCs from TNF alpha cytotoxicity in a dose-dependent manner as measured by the XTT and TUNEL assays. IGF-1 activates both the PI3/Akt and the extracellular signal-regulated kinase (ERK) pathway. However, IGF-1-enhanced cell survival signals were mediated by the PI3K/Akt, but not by the ERK pathway, as evidenced by the observation that IGF-1-enhanced cell survival was partially abrogated by Akti, the Akt inhibitor, or wortmannin, the PI3K inhibitor, but not by PD98059, the MAPK kinase/ERK kinase inhibitor. The downstream events of IGF-1-griggered survival signals included phosphorylation of BAD, blockade of TNF alpha-induced translocation of Bax from the cytosol to the mitochondrial membrane, and suppression of caspase-9 and caspase-3 activation. These observations indicate that the protection of OPCs by IGF-1 is mediated, at least partially, by interruption of the mitochondrial appoptotic pathway via activation of PI3K/Akt. (C) Wiley-Liss, Inc.