ATP and adenosine - two players in the control of seizures and epilepsy development
Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.
National Institutes of Health (NIH) through grants NS103740 & NS065957
Health Research Board HRA-POR-2015-1243
Science Foundation Ireland [17/CDA/4708 and 16/RC/3948 (co-funded under the European Regional Development Fund and by FutureNeuro industry partners)]
CommentsThe original article is available at https://www.sciencedirect.com/
Published CitationBeamer E, Kuchukulla M, Boison D, Engel T. ATP and adenosine - two players in the control of seizures and epilepsy development. Prog Neurobiol. 2021;204:102105.
Publication Date16 June 2021
- Physiology and Medical Physics
- FutureNeuro Centre
- Published Version (Version of Record)