The roles of adenosine to prevent epileptogenesis through anterior nucleus of thalamus deep brain stimulation

Abstract

Current Epilepsy therapies are inadequate as at least 30% of all patients develop pharmacoresistance and/or suffer from psychiatric comorbidities as well as significant side-effects from antiepileptic drugs. Anterior nucleus of the thalamus deep brain stimulation (ANT-DBS) was recently approved in the US and Brazil, as an alternative treatment option for patients with medically refractory focal epilepsies. Although recent clinical trials showed that a sizable number of patients with focal Epilepsy showed significant reduction in their spontaneous recurrent (SRS) seizures during ANT-DBS, its mechanisms of action are still poorly understood. By using the pilocarpine model of Temporal Lobe Epilepsy (TLE) in the rat, we have previously demonstrated that ANT-DBS reduces neuronal excitability, neuroinflammation and apoptosis, with concomitant increases in adenosine (ADO) levels in the hippocampus. In the current study, we test the hypothesis that ANT-DBS suppresses seizures through increased activation of adenosine A1R and Epilepsy development through inhibition of DNA methylation. We will use the pilocarpine model in rats to induce status epilepticus and chronic ANT-DBS to test the hypothesis that ANT-DBS (1) will prevent or delay the development of SRS (anti-epileptogenic effect), (2) will modify the hippocampal expression of ADO/ADK, and (3) leads to the suppression of DNA methylation (dependent on nuclear ADK form). The expected outcome is in the characterization of the mechanisms of action of ANT-DBS as an anti-epileptogenic and anti-ictogenic neuromodulation technique. In particular, we will determine whether the antiepileptogenic effects of ANT-DBS are specifically related to adenosine and dependent on epigenetic alterations. An understanding of the ANT-DBS mechanism of action may reveal a new class of therapies for Epilepsy and its prevention. (AU)