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 A2A (A2AAR) has been shown to possess anti-inflammatory properties that have not been studied in TON. In the present study, we examined the role of A2AAR in retinal complications associated with TON. Initial studies in wild-type mice revealed that treatment with the A2AAR agonist resulted in marked decreases in the TON-induced microglial activation, retinal cell death and releases of reactive oxygen species and pro-inflammatory cytokines TNF-α and IL-6. To further assess the role of A2AAR in TON, we studied the effects of A2AAR ablation on the TON-induced retinal abnormalities. A2AAR-/- mice with TON showed a significantly higher mRNA level of TNF-α, Iba1-1 in retinal tissue, and ICAM-1 expression in retinal sections compared with wild-type mice with TON. To explore a potential mechanism by which A2AAR-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 A2AAR attenuates hypoxia or LPS-induced TNF-α release and significantly repressed the inflammatory signaling, ERK in the activated microglia. Collectively, this work provides pharmacological and genetic evidence for A2AAR signaling as a control point of cell death in TON and suggests that the retinal protective effect of A2AAR is mediated by attenuating the inflammatory response that occurs in microglia via interaction with MAPKinase pathway.
Keywords: 2-p-[2-Carboxyethyl]phenethylamino-5′-N-ethylcarboxamidoadenosine; 4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol; 5′-N-Ethylcarboxamidoadenosine; AR; Adenosine A(2A) receptor; CGS21680; ELISA; ERK; Enzyme-linked immunosorbent assay; Inflammatory cytokines; LPS; MAP kinase; MAPKinase; Microglia; Mitogen-activated protein kinase; NECA; Oxidative stress; ROS; TNF-α; TON; Traumatic optic neuropathy; ZM241385; adenosine receptor; extracellular signal-regulated kinase; lipopolysaccharides; reactive oxygen species; traumatic optic neuropathy; tumor necrosis factor-α.
© 2013.