An adenosine A1R-A2aR imbalance regulates low glucose/hypoxia-induced microglial activation, thereby contributing to oligodendrocyte damage through NF-κB and CREB phosphorylation.

Microglial activation-mediated inflammatory damage to oligodendrocytes is a key step in the etiology of ischemic white matter lesions. The adenosine A1 receptor (A1R) and adenosine A2a receptor (A2aR) have been reported to regulate the activation of microglia, however, the underlying mechanisms remain elusive. Thus, the present study used a microglia/oligodendrocyte co‑culture model exposed to low glucose/hypoxia, and treated with agonists/antagonists of A1R and A2aR to investigate the role of A1R and A2aR. Changes in A1R and A2aR expression and inflammatory cytokine secretion by the microglia, and oligodendrocyte damage, after exposure were examined. Low glucose/hypoxia induced a higher elevation of A1R than A2aR. In addition, activation of A1R inhibited A2aR protein expression and vice versa. The A1R antagonist DPCPX (100 nM) and A2aR agonist CGS 21680 (100 nM) inhibited microglial activation, reduced the production of inflammatory cytokines and attenuated oligodendrocyte damage, along with elevating the levels of phosphorylated nuclear factor (NF)‑κB and cyclic adenosine monophosphate response element binding protein (CREB). These data indicate that an A1R‑A2aR imbalance is able to modulate low glucose‑induced microglial activation and the cellular immune response through altering NF‑κB and CREB phosphorylation. This suggests that rebalancing A1R‑A2aR is a promising approach for treating white matter injury.