Premium
IGF‐I prevents glutamate‐mediated bax translocation and cytochrome C release in O4 + oligodendrocyte progenitors
Author(s) -
Ness Jennifer K.,
Scaduto Russell C.,
Wood Teresa L.
Publication year - 2004
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10360
Subject(s) - glutamate receptor , biology , microbiology and biotechnology , kainate receptor , oligodendrocyte , ampa receptor , excitotoxicity , metabotropic glutamate receptor , metabotropic glutamate receptor 6 , apoptosis , cytochrome c , programmed cell death , nmda receptor , mitochondrion , receptor , biochemistry , neuroscience , central nervous system , myelin
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. © 2004 Wiley‐Liss, Inc.