Evaluating the adenosine hypothesis of restless legs syndrome and its implications for current and future treatment strategies

Introduction Restless Legs Syndrome (RLS) is a sensorimotor disorder linked to brain iron deficiency and dopaminergic dysfunction. Increasing evidence suggests that alterations in adenosine signaling may represent the missing link connecting dopaminergic and glutamatergic abnormalities. The ‘adenosine hypothesis’ proposes that brain iron deficiency induces a hypoadenosinergic state, primarily through adenosine A1 receptor downregulation, resulting in cortical hyperexcitability, hyperarousal, and periodic limb movements.Areas covered This critical perspective examines experimental, neurophysiological, and clinicaldata supporting the adenosine hypothesis of RLS. Findings from animal models demonstrate altered A1/A2A receptor balance in cortico-striatal terminals, promoting glutamatergic hyperactivity. In particular, neurophysiological studies further support the adenosine hypothesis, highlighting a pattern of cortical hyperexcitability and impaired inhibitory control in RLS. In this context, preliminary clinical trials with dipyridamole, an equilibrative nucleoside transporter inhibitor that enhances extracellular adenosine, showed symptomatic improvement, supporting adenosinergic enhancement as a therapeutic approach.Expert opinion The adenosine hypothesis provides an integrative framework uniting dopaminergic, glutamatergic, and iron-related mechanisms in RLS. Targeting adenosine transmission could complement existing therapies and mitigate augmentation. Future research should prioritize receptor-selective ligands, multimodal biomarkers, and controlled trials to translate this hypothesis into mechanism-based neurotherapeutic strategies.