Adenosine Dysfunction in Epilepsy and Associated Comorbidities

Epilepsy, a complex neurological syndrome with dominant symptoms and various comorbidities, affects over 70 million people worldwide. Epilepsy-related comorbidities, including cognitive and psychiatric disorders, can impede therapy for epilepsy patients, leading to heavy burdens on patients and society. Adenosine has an anti-epileptic and anticonvulsive function in the brain. Several studies have shown that, through adenosine receptor-dependent and -independent mechanisms, adenosine can influence the development and progression (epileptogenesis) of epilepsy and its associated comorbidities. As the key enzyme for adenosine clearance, adenosine kinase (ADK) can exacerbate epileptic seizures not only by accelerating adenosine clearance, but also by increasing global DNA methylation through the transmethylation pathway. Therefore, adenosine augmentation therapies for epilepsy can have dual functions in the inhibition of epileptic seizures and the prevention of its overall progress. This review has three main purposes. First, we discuss how maladaptive changes in the adenosine pathway affect the development and progress of epilepsy in both receptor-dependent and receptor-independent ways. Second, we highlight the important influence of associated comorbidities on the prognosis of epilepsy and explore the role of adenosine in these comorbidities. Finally, we emphasize the potential of adenosine augmentation therapies in restoring normal adenosine signaling in the epileptic brain. Such treatments could effectively improve the prognosis of patients who are resistant to most antiepileptic drugs (AEDs), and thus bring new challenges and opportunities in the treatment of epilepsy patients.