Abstract
In traumatic optic neuropathy (TON), apoptosis of retinal ganglion cells is closely related to the local production of reactive oxygen species and inflammatory mediators from activated microglial cells. Adenosine receptor A(2A) (A(2A)AR) has been shown to possess anti-inflammatory properties that have not been studied in TON. In the present study, we examined the role of A(2A)AR in retinal complications associated with TON. Initial studies in wild-type mice revealed that treatment with the A(2A)AR agonist resulted in marked decreases in the TONinduced microglial activation, retinal cell death and releases of reactive oxygen species and pro-inflammatory cytokines TNF-a and IL-6. To further assess the role of A(2A)AR in TON, we studied the effects of A(2A)AR ablation on the TON-induced retinal abnormalities. A(2A)AR /mice with TON showed a significantly higher mRNA level of TNF-a, Ibal-1 in retinal tissue, and ICAM-1 expression in retinal sections compared with wild-type mice with TON. To explore a potential mechanism by which A(2A)AR-signaling regulates inflammation in TON, we performed additional studies using hypoxia- or LPS-treated microglial cells as an in vitro model for TON. Activation of A(2A)AR attenuates hypoxia or LPS-induced TNF-a release and significantly repressed the inflammatory signaling, ERK in the activated microglia Collectively, this work provides pharmacological and genetic evidence for A(2A)AR signaling as a control point of cell death in TON and suggests that the retinal protective effect of A(2A)AR is mediated by attenuating the inflammatory response that occurs in microglia via interaction with MAPKinase pathway. (C) 2013 Elsevier B.V. All rights reserved.