IGF‐I prevents glutamate‐mediated bax translocation and cytochrome C release in O4⁺oligodendrocyte progenitors

Abstract

Oligodendroglial death due to overactivation of the AMPA/kainate glutamate receptors is implicated in white matter damage in multiple CNS disorders. We previously demonstrated that glutamate induces caspase-3 activation and death of the late oligodendrocyte progenitor known as the pro-oligodendroblast (pro-OL) via activation of the AMPA/kainate glutamate receptors. We also demonstrated that IGF-I had the unique ability to sustain activation of Akt in the pro-OL and provide long-term protection of these cells from glutamate-mediated apoptosis. The goal of these studies was to investigate the mechanisms of glutamate toxicity and IGF-I-mediated survival in the pro-OL. IGF-I prevented glutamate-induced loss of mitochondrial membrane potential, cytochrome c release, and caspase-9 activation. In contrast to IGF-I mediated survival mechanisms in neurons, IGF-I had no effect on the influx or recovery of intracellular calcium levels or on levels of major pro- and anti-apoptotic molecules including Bax or Bcl-xL. Rather, IGF-I prevented the glutamate-induced translocation of Bax to the mitochondria. Moreover, IGF-I prevented caspase-3 activation in pro-OLs as long as 8 h after exposure of the cells to glutamate, suggesting that delayed activation of IGF-I-mediated survival pathways can block glutamate-mediated apoptosis in pro-OLs. The results of these experiments define the mechanisms by which glutamate kills oligodendrocyte progenitor cells and by which IGF-I blocks glutamate-induced apoptosis in these cells. The data also demonstrate that IGF-I disrupts the glutamate-mediated apoptotic pathway in the pro-OL through mechanisms that are distinct from its survival-promoting actions in neurons.

Hypoxia—Ischemia Preferentially Triggers Glutamate Depletion from Oligodendroglia and Axons in Perinatal Cerebral White Matter

“…Early cells of the human oligodendroglial lineage are a primary target of injury in PWMI (Back et al, 2005;Haynes et al, 2003). Major features of the early degeneration of these cells have been replicated in perinatal rodent models of acute hypoxiaischemia (Back et al, 2002a;Follett et al, 2000;Lin Ness et al, 2004;Ness and Wood, 2002). The evidence linking glutamatemediated excitotoxicity to degeneration of early cells of the oligodendrocyte lineage is strong, and we have now defined the potential cellular pools of glutamate that are available for release in perinatal rat periventricular white matter, and have assayed how these sources of glutamate are affected by a relatively brief period of hypoxia-ischemia.…”

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

“…Indeed, a survival activity has been documented for bFGF, PDGF-B, VEGF, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and erythropoietin for hypoxic neurons (15,(35)(36)(37)(38)(39)(40)(41), acidic fibroblast growth factor, IGF-I and erythropoietin for hypoxic myocardial cells (42)(43)(44)(45)(46), VEGF for hypoxic chondrocytes (47), or hepatocyte growth factor and erythropoietin for hypoxic renal cells (48,49). Growth factors may also protect cells against apoptosis in response to other stimuli, as exemplified by the ability of erythropoietin, c-kit ligand, or interleukin-3 to block p53-mediated apoptosis of hematopoietic cell lines (50 -52) by the protective effect of IGF-I or EGF on epithelial cells or lymphocytes against Fas-induced apoptosis (53)(54)(55) or by the inhibition by IGF-I of glutamateinduced apoptosis of oligodendrocyte progenitors (56). In addition, IGF-1 and PDGF inhibit apoptosis of fibroblasts during serum starvation (57), whereas VEGF protects HepG2 and endothelial cells against apoptosis induced by TNF-␣ or serum deprivation (25,58).…”

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

“…47,48 Also, in pro-OLs, pro-apoptotic Bax translocation into mitochondria is a glutamate-mediated event that can be prevented by IGF-1. 49 Additionally, OPC vulnerability to excitotoxicity mediated by calcium influx is also influenced by the fact that (1) the particular GluR subunits expressed in OPCs are those that confer high calcium permeability 50,51 and (2) OPCs (unlike neurons) do not express calcium-binding proteins for maintenance of intracellular calcium homeostasis. 52 ROS and cellular defenses.…”