Adenosine receptors as emerging therapeutic targets in epilepsy

Epilepsy is one of the most prevalent neurological disorders, and approximately one-third of patients remain resistant to current pharmacological treatments. This underscores the urgent need for innovative therapeutic strategies targeting novel molecular pathways. Among G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have emerged as promising candidates due to their central role in regulating neuronal excitability, neurotransmitter release, and neuroinflammation. Four AR subtypes (A1R, A2AR, A2BR, and A3R) exhibit distinct expression profiles and signaling mechanisms, enabling both neuroprotective and neuromodulatory functions. Preclinical studies have demonstrated that modulation of ARs can attenuate seizures, reduce epileptogenesis, and provide neuroprotection in various models of epilepsy. However, the therapeutic translation of AR-targeting agents has been hampered by challenges such as narrow therapeutic windows and off-target cardiovascular effects. Recent advances, including the development of highly selective agonists, antagonists, biased ligands, and positive allosteric modulators provide new opportunities for precision therapy. This review summarizes current knowledge on AR biology, their involvement in epileptogenesis, and the therapeutic potential of AR modulators, highlighting both the promise and limitations of targeting adenosine signaling in epilepsy and related neurological disorders.