The Ying and Yang of Adenosine A1 and A2A Receptors on ERK1/2 Activation in a Rat Model of Global Cerebral Ischemia Reperfusion Injury

Adenosine impacts cerebral ischemia reperfusion (IR) through the inhibitory A(1) and the excitatory A(2) receptors. The present study aimed at investigating the contrasting role of pERK1/2 in mediating adenosine A(1)R (protective) versus A(2A)R (deleterious) effects in IR. Male Wistar rats subjected to bilateral carotid occlusion (45 min) followed by reperfusion (24 h) exhibited increased pERK1/2 activity, downstream from DAG pathway, along with increases in hippocampal glutamate, c-Fos, NF-kappa B, TNF-alpha, iNOS, TBARS, cytochrome c, caspase-3, BDNF, Nrf2, and IL-10 contents. Further, hippocampal microglial reactivity, glial TNF-alpha, and BDNF expression were observed. Although unilateral intrahippocampal injection of either the A(1)R agonist CHA or the A(2A)R agonist CGS21680 increased pERK1/2, only CHA mitigated histopathological and behavioral deficits along with reducing glutamate, microglial activation, c-Fos, TNF-alpha, iNOS, TBARS, cytochrome c and caspase-3 and elevating Nrf2 and IL-10 levels in IR rats. These results yield insight into the double-faceted nature of pERK1/2 in mediating protective and deleterious effects of A(1)R and A(2A)R signaling, respectively, against IR injury.