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-X(L) 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-X(L), and by preventing Bax translocation to the mitochondria.
Department of Emergency Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Thomas H
TH
Sanderson
Rita
R
Kumar
Jonathon M
JM
Sullivan
Gary S
GS
Krause
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D045304:Cytochromes c / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007328:Insulin / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
D007328:Insulin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases