The Effects of Adenosine A1/A3 Receptors Agonist on Improving the Outcomes of TBI and Stroke: Focus on AST-004

Purpose of Review: This review explores the therapeutic potential of dual adenosine A1 and A3 receptor (A1R/A3R) agonism as a neuroprotective treatment for acute ischemic stroke (AIS) and traumatic brain injury (TBI). Current AIS treatments, tissue plasminogen activator and mechanical thrombectomy, are limited by narrow therapeutic windows and strict eligibility criteria. In contrast, TBI management remains primarily supportive, with no Food and Drug Administration-approved therapies targeting the underlying molecular pathology. Dual A1R/A3R agonists offer a new approach by modulating injury pathways at the cellular level, potentially serving as an adjunct or alternative to existing therapeutic options. Recent Findings: A1R and A3R are G protein-coupled receptors that control neuroinflammation, excitotoxicity, and metabolic balance. Preclinical studies using rodent and non-human primate models of AIS and TBI have shown that dual A1R/A3R agonists reduce infarct size, slow lesion growth, preserve penumbral tissue, and enhance neurological recovery. These effects are mediated through astrocyte activation, support of mitochondrial function, and suppression of pro-inflammatory cytokines. The neuroprotective effects follow a U‑shaped dose–response pattern, where only intermediate doses provide benefit, whereas lower and higher doses are less effective. Compared to monotherapies, A1R/A3R agonists activate multiple overlapping pathways, including neurotransmitter regulation, apoptosis control, and blood-brain barrier function. Summary: Dual A1R/A3R agonists are a promising and adaptable neuroprotective strategy for both AIS and TBI. Their wide-ranging mechanism offers benefits beyond current revascularization options, especially for patients ineligible for tPA or thrombectomy. Early-phase data indicate strong translational potential, and ongoing trials will determine whether these results translate into improved clinical outcomes. Given the urgent need for effective neuroprotectants, A1R/A3R agonists could become an essential component of neurocritical care. AST-004 has recently advanced into a Phase II clinical evaluation, with ongoing assessments of its safety and effectiveness in humans.