Modulation of Ischemic Brain Injury and Neuroinflammation by Adenosine A2A Receptors

Jiang-Fan      Chen; Felicita      Pedata

Abstract

Over the past 5 years, the adenosine A2A receptor (A2AR) is emerging as an attractive therapeutic target for modulating brain injury in a variety of animal models of neurological disorders including stroke. The evidence we have to date indicates that both adenosine and A2A antagonists are neuroprotective in ischaemic brain injury. From drug development perspective, administering A2A antagonists in association with inhibitors of adenosine kinase may represent a novel strategy for treating stroke. Despite the well-documented neuroprotection by A2AR antagonists, the mechanism by which A2ARs affect brain injury remains largely unknown. In this section, we also summarize the experimental evidence for A2AR modulation of glial function as possible contribution to the modulation of brain injury. In vitro and in vivo studies reveal that in response to local neuroinflammation following brain insults, time-dependent, inflammatory signal-mediated induction of the A2AR in glial cells (particularly microglial cells) make this cell type particularly sensitive to A2AR modulation of brain injury. Furthermore, in contrast to the generally held view that the A2AR exerts predominantly anti-inflammatory effects (based upon studies in peripheral organs), the A2AR modulation of neuroinflammation may differentially affect the outcome of brain injury, depending on the nature of brain insults. Thus, in association with their ability to reduce brain injury, inactivation of the A2AR in most models and activation of A2AR in some cases have been shown to attenuate brain inflammation through control of the proliferation and production of proinflammatory cytokines,

Keywords: Adenosine, adenosine A2A receptor, neuroprotection, ischemia, neuroinflammation, excitoxicity, microglia, astrocytes, bone marrow derived cells