Role of protein kinase Akt in cerebral ischemia

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Protein kinase B/Akt is a serine-threonine kinase which acts downstream of phosphatidylinositol 3-kinase (PI3K) and is induced by many endogenous ligands such as IGF-1, FGF, steroid hormones, and statins. Phosphorylation of Akt leads to modulation of a variety of signal pathways with potential neurovascular protective effects including inactivation of glycogen synthase kinase (GSK)-3beta, activation of glucose transporter (Glut)-4, and inhibition of caspase-9. Indeed, activation of Akt has been shown to increase cell growth, improve glucose metabolism, and to reduce neuronal apoptosis. However, the role of Akt regulating ischemia-induced changes in cerebrovascular tone, cortical spreading depression, inflammation, BBB permeability, and neuronal cell death is not known. Recent studies have focused on the activation of endothelial nitric oxide synthase (eNOS) via the PI3K/Akt pathway. Akt phosphorylates eNOS at Ser 1179, leading to increased eNOS activity and NO production. Endothelium-derived NO may be neuroprotective due to its vasodilating, anti-inflammatory, and antioxidative properties. Activation of Akt in the neurovascular unit, therefore, may be a promising therapeutic target for attenuating cerebrovascular injury. Although Akt could potentially play a pivotal role in cerebral ischemia by improving neurovascular function, the specific role of endothelial and neuronal Akt in mediating the neurovascular unit's response to cerebral ischemia has not yet been determined. This limitation is mostly due to the lack of pharmacological tools available for a tissue-specific modulation of Akt. Consequently, a genetic approach using tissue-restricted targeted gene disruption or modulation is more likely to elucidate the specific function of Akt in the endothelium and CNS. For this purpose, we have developed transgenic mice overexpressing constitutively-active or dominant-negative mutants of Akt, which are inducibly targeted to the endothelium and CNS using the Cre/IoxP system. Three specific aims are proposed, which will investigate the role of endothelial and neuronal Akt in mediating the neurovascular unit's response to cerebral ischemic injury and determine whether Akt mediates the neuroprotective effects of statins, steroid hormones, and growth factors.