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3.
Mol Cell Neurosci ; 24(4): 1027-37, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14697666

RESUMEN

Recent 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 Ser(307) 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 ( approximately 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.


Asunto(s)
Ácido Glutámico/toxicidad , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Masculino , Ratas , Ratas Wistar , Transducción de Señal/fisiología
4.
Neuroreport ; 12(6): 1293-6, 2001 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-11338209

RESUMEN

Neurotrophic factors modulate synaptic plasticity through mechanisms that include regulation of membrane ion channels and neurotransmitter receptors. Recently, it was shown that insulin-like growth factor I (IGF-I) induces depression of AMPA-mediated currents without affecting NMDA-receptor function in neurons. We now report that IGF-I markedly potentiates the kainate-preferring ionotropic glutamate receptor in young cerebellar granule neurons expressing functional kainate-, but not AMPA-mediated currents. Potentiation of kainate responses by IGF-I is blocked by wortmannin, a phosphatidylinositol 3-kinase (P13K) inhibitor, indicating a role for this kinase in the effect of IGF-I. These results reinforce the notion that modulation of ionotropic glutamate receptors are involved in the regulatory actions of IGF-I on neuronal plasticity.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/fisiología , Receptores de Ácido Kaínico/fisiología , Transducción de Señal/fisiología , Androstadienos/farmacología , Animales , Inhibidores Enzimáticos/farmacología , Plasticidad Neuronal/fisiología , Ratas , Ratas Wistar , Wortmanina
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