Emerging Roles of Adenosine Metabolism in Astrocytes During Brain Injury

OBJECTIVE: Adenosine is a key metabolic and neuroregulatory factor in the brain, and an adenosine-rich immunosuppressive microenvironment is formed post-stroke, making the adenosine pathway a crucial therapeutic target for improving stroke immunotherapy efficacy. This study aims to address the knowledge gaps hindering adenosine therapy translation, summarize the integrated network of extracellular and intracellular adenosine metabolism, and highlight the dynamic changes of adenosine metabolism in astrocytes and the potential of purine-converting enzymes as therapeutic targets for cerebral ischemic stroke. METHODS: We conducted a comprehensive summary and analysis of existing research progress over the past two decades, focusing on adenosine metabolic networks (extracellular and intracellular), adenosine metabolic enzymes, subcellular compartmental metabolic pathways, dynamic changes of adenosine metabolism in astrocytes during brain injury, and the role of purine-converting enzymes in cerebral ischemic stroke. We also reviewed the limitations of current adenosine-related therapies (e.g., P2Y12-targeted drugs) and existing knowledge gaps. RESULTS: Post-stroke, dying and stressed neuronal cells increase ATP release, which is converted to adenosine by extracellular enzymes, forming an adenosine-rich immunosuppressive microenvironment. P2Y receptors (a type of ADP receptor) have been extensively studied as vital drug targets for ischemic stroke, but treatments such as Ticagrelor (targeting P2Y12) are associated with severe bleeding. Key knowledge gaps include the lack of cell type-specific regulation of the adenosine pathway in the brain and insufficient consideration of cell compartmentalized adenosine metabolism. Additionally, astrocyte adenosine metabolism undergoes dynamic changes during brain injury, and purine-converting enzymes exhibit potential as novel therapeutic targets for cerebral ischemic stroke. CONCLUSIONS: Adenosine metabolism forms an integrated complex network involving extracellular and intracellular processes, with distinct metabolic enzymes and subcellular compartmental pathways. Dynamic changes of adenosine metabolism in astrocytes and purine-converting enzymes are critical for the development of adenosine-based therapies for cerebral ischemic stroke. Addressing existing knowledge gaps (e.g., cell type-specific regulation and compartmentalized metabolism) is essential to overcome current clinical trial difficulties and promote the translation of adenosine therapy for stroke.