Adenosine-A2 Receptor Signaling in Astrocytes Mitigates Cerebral Ischemic Injury via Suppressing Glutamate-Induced Excitotoxicity

Excitotoxicity constitutes a core pathological mechanism in cerebral ischemia and other central nervous system disorders. Astrocytes serve as pivotal regulators of glutamate–glutamine cycle homeostasis and thereby play a critical role in mitigating excitotoxicity. This study established a rat thromboembolic stroke model via autologous thrombus induction and systematically investigated the mechanisms underlying adenosine-mediated neuroprotection through pharmacological modulation of the adenosine pathway using adenosine, dipyridamole, and selective adenosine receptor antagonists. Subsequently, light-sensitive opsin expression in astrocytes was driven by the GFAP promoter, enabling cell-type-specific optogenetic modulation of astrocyte activity. Our findings demonstrate that adenosine significantly attenuates cerebral injury in a rat model of thromboembolic stroke, with astrocytes identified as the primary cellular target. Adenosine elicits an anti-excitotoxic effect by coordinately upregulating GLT-1 protein expression and downregulating Cx43 protein expression in astrocytes, thereby regulating glutamate transport and diffusion. Moreover, our findings demonstrate that adenosine-mediated neuroprotection is significantly attenuated by SCH58261 but not by PSB1115. We conclude that the adenosine–A2A receptor system plays a critical role in the regulation of glutamate homeostasis.