Thursday, May 2, 2024
5/2/2024
PROJECT SUMMARY Preventing epilepsy and its progression (epileptogenesis) remains the ultimate goal for epilepsy research and therapy development. Although this has been identified as an urgent need by the NINDS Epilepsy Research Benchmarks, there is still no therapy available that interferes with the epileptogenic process. The development of a therapy to prevent epilepsy and its progression would be paradigm-shifting in the way epilepsy, one of the most frequent neurological conditions worldwide, would be treated. This application is designed to test new interventional therapies to prevent epilepsy in rodent models of acquired epilepsy utilizing existing FDA- approved drugs. The rationale for our approach is based on more than 25 years of research into maladaptive processes in adenosine metabolism, which drive, and contribute to, the epileptogenic process that turns a healthy brain into an epileptic brain. Specifically, an acute injury-associated adenosine surge in the brain drives glial activation and dysregulation of glutamate homeostasis through increased activation of adenosine A2A receptors, which couple to the astroglial glutamate transporter GLT-1. Hence, the use of the FDA approved A2A receptor blocker istradefylline, or the FDA approved GLT-1 activator ceftriaxone are rational therapeutic interventions to interfere with key mechanisms during the onset of the epileptogenic cascade. A delayed response of the epileptogenic cascade is pathological overexpression of the major adenosine metabolizing enzyme adenosine kinase (ADK) resulting in chronic adenosine deficiency in the epileptic brain. We have shown that overexpression of ADK, and specifically an isoform expressed in the cell nucleus (ADK-L), drives the epileptogenic process through an epigenetic mechanism (increased DNA methylation). We have shown that therapeutic adenosine augmentation effectively prevents epilepsy and its progression in 4 different rodent models of epileptogenesis. Hence ADK inhibitors and DNA methylation blockers (e.g. the FDA approved drug - 5-azacytidine) hold promise for the prevention of epilepsy and its progression. To this end we recently launched a drug discovery program, which yielded a candidate ADK-L inhibitor (MRS-4203) with antiepileptogenic activity. Collectively, our preliminary data provide a solid rationale that the adenosine system and its downstream mediators offer several possible antiepileptogenic therapeutic targets. The CENTRAL GOAL of this application is to identify and test therapeutic strategies for epilepsy prevention based on repurposing of FDA approved drugs and the use of novel small molecule compounds that target components of the adenosinergic system. Our therapeutic approaches will be tested and optimized in the mouse intrahippocampal kainic acid model of temporal lobe epilepsy and validated in a traumatic brain injury induced model of posttraumatic epilepsy. Our hypothesis will be addressed in three Specific Aims: (1) Targeting adenosine receptor dependent mechanisms for epilepsy prevention (2) Targeting adenosine receptor independent mechanisms for epilepsy prevention (3) Test therapeutic efficacy of antiepileptogenic combination therapies
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