Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia.

Unlabelled: Insulin is neuroprotective following transient global brain ischemia; however, the mechanisms by which insulin exerts its salutary effects remain unclear.

Objective: We assessed insulin's effect on the PI3K-Akt survival system and consequent modulation of the pro-apoptotic proteins Bim, Bad and FoxO3a.

Methods: We utilized rats subjected to 10 minutes of global brain ischemia, with or without insulin administered at the onset of reperfusion.

Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia.

Upon brain reperfusion following ischemia, there is widespread inhibition of neuronal protein synthesis that is due to phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), which persists in selectively vulnerable neurons (SVNs) destined to die. Other investigators have shown that expression of mutant eIF2alpha (S51D) mimicking phosphorylated eIF2alpha induces apoptosis, and expression of non-phosphorylatable eIF2alpha (S51A) blocks induction of apoptosis. An early event in initiating apoptosis is the release of cytochrome c from mitochondria, and cytochrome c release corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia.