Adenosine kinase is a new therapeutic target to prevent ischemic neuronal death

The brain has evolved several endogenous mechanisms to protect itself from the deleterious consequences of stroke. One of those endogenous neuroprotective systems is centered on the purine ribonucleoside adenosine, which exerts potent neuroprotective functions within the brain. One major goal in therapeutic stroke research is to explore and utilize such endogenous neuroprotective mechanisms therapeutically. This review illustrates molecular approaches to study the role of the adenosine system within the context of stroke and highlights innovative therapeutic approaches aimed at increasing adenosinergic function. New research data suggest that the major adenosine regulating enzyme adenosine kinase (ADK) plays a prominent role in determining the brain's susceptibility to ischemic injury. Thus, endogenous ADK is rapidly downregulated following a stroke, possibly an endogenous neuroprotective mechanism aimed at raising ambient levels of adenosine in brain. Conversely, transgenic overexpression of ADK in brain renders the brain more susceptible to stroke-induced neuronal cell loss. In the present review we will first summarize the physiological role of adenosine metabolism within the context of ischemic brain injury. Next, we will highlight the key role of ADK in determining the brain's susceptibility to ischemic injury, and finally we will discuss potential therapeutic applications of adenosine augmentation to provide neuroprotection in stroke.