Akt: it's role in neuronal viability and protection against ischemia in the rat hippocampus

Abstract

According to the American Stroke Association, about 700,000 people suffer a new or recurrent stroke each year in the United States. Of these people, approximately 163,000 die, making stroke the third leading cause of death in the U.S., only behind heart disease and cancer. Depending on the area of the brain affected by the stroke, functions such as motor activity, speech, behavior, and/or memory can be hampered. The hippocampus is a bilateral structure that is highly susceptible to hypoxic and/or ischemic insult.

One of the early responses to ischemia is the transient and reversible inhibition of synaptic activity mediated by endogenous adenosine acting on neuronal A1 receptors. Increase in adenosine during ischemia is thought to play a key prosurvival role by attenuating excitotoxic damage through inhibiting glutamate release and activating Akt.

Akt is activated by PI3K-dependent and PI3K-independent mechanisms. Akt, also known as PKB, has been shown to be both necessary and sufficient to promote cell survival by growth factors in vitro. Akt directly phosphorylates multiple proteins resulting in the inhibition of apoptotic and/or necrotic cell death. Bcl-2 and Bcl-xL are two proteins that are disinhibited by the direct Akt phosphorylation of Bad. These two proteins function to maintain mitochondrial integrity during ischemia, thus inhibiting the release of cytochrome c which is a strong inducer of the apoptotic pathway.

This thesis explores the activation mediated by PI3K and the significance of this activation in neuronal survival mechanisms.