The Ying and Yang of Adenosine A and A 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 and the excitatory A receptors. The present study aimed at investigating the contrasting role of pERK1/2 in mediating adenosine AR (protective) versus AR (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-κB, TNF-α, iNOS, TBARS, cytochrome c, caspase-3, BDNF, Nrf2, and IL-10 contents. Further, hippocampal microglial reactivity, glial TNF-α, and BDNF expression were observed. Although unilateral intrahippocampal injection of either the AR agonist CHA or the AR agonist CGS21680 increased pERK1/2, only CHA mitigated histopathological and behavioral deficits along with reducing glutamate, microglial activation, c-Fos, TNF-α, 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 AR and AR signaling, respectively, against IR injury.