Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding |
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Authors: | Sanderson Thomas H Kumar Rita Sullivan Jonathon M Krause Gary S |
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Affiliation: | Department of Emergency Medicine, Wayne State University, Detroit, Michigan, USA; Department of Physiology, Wayne State University, Detroit, Michigan, USA; Department of Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA |
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Abstract: | The critical event of the intrinsic pathway of apoptosis following transient global brain ischemia is the release of cytochrome c from the mitochondria. In vitro studies have shown that insulin can signal specifically via phosphatidylinositol-3-OH-kinase (PI3-K) and Akt to prevent cytochrome c release. Therefore, insulin may exert its neuroprotective effects during brain reperfusion by blocking cytochrome c release. We hypothesized that insulin acts through PI3-K, Akt, and Bcl-2 family proteins to inhibit cytochrome c release following transient global brain ischemia. We found that a single bolus of insulin given immediately upon reperfusion inhibited cytochrome c release for at least 24 h, and produced a fivefold improvement in neuronal survival at 14 days. Moreover, insulin's ability to inhibit cytochrome c release was completely dependent on PI3-K signaling and insulin induces phosphorylation of Akt through PI3-K. In untreated animals, there was an increase in mitochondrial Bax at 6 h of reperfusion, and Bax binding to Bcl-XL was disrupted at the mitochondria. Insulin prevented both these events in a PI3-K-dependent manner. In summary, insulin regulates cytochrome c release through PI3-K likely by activating Akt, promoting the binding between Bax and Bcl-XL, and by preventing Bax translocation to the mitochondria. |
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Keywords: | Bax cytochrome c hippocampus insulin ischemia neuroprotection |
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