Role of adenosine A2A receptors in cerebral ischemia

The extracellular concentration of adenosine in the brain increases dramatically during ischemia due to degradation of extracellularly released ATP in the first minutes after stroke and to adenosine released per se from cells. Adenosine A2a receptor is expressed in neurons and glial cells and in peripheral inflammatory cells (lymphocytes and granulocytes). Adenosine A2a receptor emerged as a potential therapeutic attractive target in ischemia. lschemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, that upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is recognized as the predominant mechanism of secondary brain injury progression. Adenosine A2A receptors present on central cells and on blood peripheral cells account for important effects depending on the time-related evolution of the pathological condition. Evidence indicate that A2a antagonists provide early protection via centrally-mediated control of excessive excitotoxicity, while A2a agonists provide protection by controlling massive blood cell infiltration in the hours and days after ischemia.