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Título

Glutamate excitotoxicity attenuates insulin-like growth factor-i prosurvival signaling

AutorGarcia-Galloway, E.; Arango, César; Pons, S.; Torres Alemán, Ignacio
Palabras claveInsulin/insulin-like growth factor I (IGF-I) Neurodegeneration
Fecha de publicación2003
EditorAcademic Press
CitaciónMolecular and Cellular Neurosciences 24: 1027- 1037 (2003)
ResumenRecent evidence suggests that impaired insulin/insulin-like growth factor I (IGF-I) input may be associated to neurodegeneration. Several major neurodegenerative diseases involve excitotoxic cell injury whereby excess glutamate signaling leads to neuronal death. Recently it was shown that glutamate inactivates Akt, a serine-kinase crucially involved in the prosurvival actions of IGF-I. We now report that excitotoxic doses of glutamate antagonize Akt activation by IGF-I and inhibit the neuroprotective effects of this growth factor on cultured neurons. Glutamate induces loss of sensitivity to IGF-I by phosphorylating the IGF-I receptor docking protein insulin-receptor-substrate (IRS)-1 in Ser307 through a pathway involving activation of PKA and PKC in a hierarchical fashion. Administration of Ro320432, a selective PKC inhibitor, abrogates the inhibitory effects of glutamate on IGF-I-induced Akt activation in vitro and in vivo and is sufficient to block the neurotoxic action of glutamate on cultured neurons. Notably, administration of Ro320432 after ischemic insult, a major form of excitotoxic injury in vivo, results in a marked decrease (~50%) in infarct size. Therefore, uncoupling of IGF-I signaling by glutamate may constitute an additional route contributing to excitotoxic neuronal injury. Further work should determine the potential use of PKC inhibitors as a novel therapeutic strategy in ischemia and other excitotoxic insults. © 2003 Elsevier Inc. All rights reserved.
URIhttp://hdl.handle.net/10261/153845
DOI10.1016/j.mcn.2003.08.005
Identificadoresdoi: 10.1016/j.mcn.2003.08.005
issn: 1044-7431
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