Adenosine and Oxygen/Glucose Deprivation in the Brain

Abstract

Extracellular adenosine concentrations in the brain increase dramatically during ischemia in concentrations that able to stimulate all (A 1 , A 2A , A 2B , and A 3) receptors. Adenosine exerts a clear neuroprotective effect through A 1 receptors during ischemia mainly by reducing precocious excitotoxic phenomena. Unfortunately, the use of selective A 1 agonists is hampered by undesirable peripheral effects. Evidence indicates that A 2A receptor antagonists administered early after ischemia provide protection centrally by reducing excitotoxicity. After ischemia, the 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 and blood cell infiltration. Evidences are that agonists at A 2A, A 2B , and A 3 receptors mainly acting on blood and vascular endothelial cells provide protection by controlling neuroinflammation, endothelial leaking, and massive blood cell infiltration in the hours and days after brain ischemia. Since ischemia is a multifactorial pathology characterized by different events evolving in the time and protracted neuroinflammation is recognized as the predominant mechanism of secondary brain injury progression, adenosinergic drugs aimed at dampening damage in the hours/days after ischemia appear promising.