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Insulin blocks cytochrome c release in the reperfused brain through PI3‐K signaling and by promoting Bax/Bcl‐XL binding

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.