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Insulin/PI3K signaling protects dentate neurons from oxygen–glucose deprivation in organotypic slice cultures
Author(s) -
Sun Xiaolu,
Yao Hang,
Douglas Robert M.,
Gu Xiang Q.,
Wang Juan,
Haddad Gabriel G.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06450.x
Subject(s) - protein kinase b , neuroprotection , pi3k/akt/mtor pathway , insulin receptor , insulin , biology , glutamate receptor , endocrinology , medicine , insulin resistance , signal transduction , microbiology and biotechnology , neuroscience , receptor , biochemistry
It is known that ischemia/reperfusion induces neurodegeneration in the hippocampus in a subregion‐dependent manner. This study investigated the mechanism of selective resistance/vulnerability to oxygen–glucose deprivation (OGD) using mouse organotypic hippocampal cultures. Analysis of propidium iodide uptake showed that OGD‐induced duration‐ and subregion‐dependent neuronal injury. When compared with the CA1–3 subregions, dentate neuronal survival was more sensitive to inhibition of phosphatidylinositol 3‐kinase (PI3K)/Akt signaling under basal conditions. Dentate neuronal sensitivity to PI3K/Akt signaling activation was inversely related to its vulnerability to OGD‐induced injury; insulin/insulin‐like growth factor 1 pre‐treatment conferred neuroprotection to dentate neurons via activation of PI3K/Akt signaling. In contrast, CA1 and CA3 neurons were less sensitive to disruptions of endogenous PI3K/Akt signaling and protective effects of insulin/insulin‐like growth factor 1, but more vulnerable to OGD. OGD‐induced injury in CA1 was reduced by inhibition of NMDA receptor or mitogen‐activated protein kinase signaling, and was prevented by blocking NMDA receptor in the presence of insulin. The CA2 subregion was distinctive in its response to glutamate, OGD, and insulin, compared with other CA subregions. CA2 neurons were sensitive to the protective effects of insulin against OGD‐induced injury, but more resistant to glutamate. Distinctive distribution of insulin receptor β and basal phospho‐Akt was detected in our slice cultures. Our results suggest a role for insulin signaling in subregional resistance/vulnerability to cerebral ischemia.