Adenosine and Oxygen/Glucose Deprivation in the Brain

Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia, primary damage due to 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. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. Extracellular concentrations of adenosine in the brain increase dramatically during ischemia at levels able to stimulate all (A1, A2A, A2B and A3) receptors. Although adenosine exerts a clear neuroprotective effect through A1 receptors during ischemia, the use of selective A1 agonists is hampered by undesirable peripheral effects. Evidence up to now in the literature indicates that A2A receptor antagonists provide protection centrally by reducing excitotoxicity, while agonists at A2A (and possibly also A2B) and A3 receptors provide protection by controlling massive infiltration and neuroinflammation in the hours and days after brain ischemia.