Role of Adenosine Receptor A2A in Traumatic Optic Neuropathies.

摘要

Traumatic optic neuropathy (TON) is a type of injury commonly seen in the war. There are currently no proven treatments that reverse the damage in TON. The proposed mechanism of TON involves optic nerve injury-induced activation of retinal microglial cells and their release of pro-inflammatory cytokines, and retinal ganglion cell (RGC) death. As a self-defense system, activated microglial cells also release adenosine, which attenuates inflammation via adenosine receptors (AR)s, including A2AAR. Although AR agonists attenuate inflammation, the way to minimize nonspecific effects associated with systemic administration of these agonists remains unclear. Released adenosine levels in the injured brain are mainly regulated by adenosine kinase (AK). Inhibition of AK potentiates local extracellular adenosine levels at cell and tissue sites which are undergoing accelerated adenosine release. Thus, AK inhibition represents a mechanism to selectively enhance the endogenous protective actions of adenosine during cellular stress. Our studies have shown that microglial activation, retinal inflammation, and RGC death occur in the mouse model of TON, and that A2AAR signaling provides protection from TON. Further, our preliminary data suggest that AK inhibitor (AKI)-enhanced A2AAR signaling provides protection from TON in mice. Therefore, inhibition of AK potentially amplifies the therapeutic effects of site- and event-specific accumulation of extracellular adenosine, which is of highly translational impact.