Adenosine is considered an endogenous neuroprotective metabolite that through activation of the A 1 receptor results in reduction of neuronal damage following cerebral ischemia. Protein kinase B, also known as Akt/PKB, is part of an endogenous pathway that exerts effective neuroprotection from both necrotic and apoptotic cell death. Using a rat model of unilateral common carotid artery occlusion coupled with hypoxia, and using in vitro rat hippocampal slices, we examined the ability of adenosine to directly activate Akt/PKB. Western blot analysis revealed that levels of phosphorylated Akt/PKB were elevated in vivo under ischemic conditions in an adenosine A 1 -dependent manner and elevated in hippocampal slices treated with an adenosine A 1 agonist. We conclude from these studies that the activation of an adenosine A 1 receptor-mediated signal transduction pathway, either by endogenous adenosine (in vivo) or by an adenosine A 1 agonist (in vitro), results in the activation of the neurotrophic kinase Akt/PKB.