Targeting Adenosine Kinase for the Prevention of Post-Traumatic Epilepsy

Epilepsy and its progression can be prevented by transient therapeutic increases of adenosine, which is the brain's own seizure regulator. Therapeutic increases in adenosine can most effectively be achieved by pharmacologically blocking the major adenosine removing enzyme: adenosine kinase (ADK). This application is built on repeated published evidence in five different animal models of epilepsy that adenosine has epilepsy preventing properties. We have previously shown that a form of ADK expressed in the cell nucleus has a specific role to regulate DNA methylation, which plays an important role in epilepsy development. This application builds on a prior Department of Defense-funded and published study, in which we demonstrated robust epilepsy prevention rats through the transient (10 days only) use of adenosine delivered by a brain implant. This application is designed to provide a mechanistic framework for the future clinical development of adenosine-based epilepsy prevention therapies. Epilepsy is a devastating disorder affecting over 3 million adults in the United States alone. A significant proportion of epilepsies are acquired, implying that those epilepsies are caused by a precipitating injury, such as traumatic brain injury (TBI). Such epilepsies are referred to as post-traumatic epilepsy (PTE) and account for 20% of all symptomatic epilepsies. Unsurprisingly, active Service Members and Veterans are at higher risk of developing epilepsy than the public because they are more likely to have TBI. The Veterans Health Administration estimated the prevalence of Veterans with epilepsy under treatment at Department of Veterans Affairs (VA) facilities to be 13.8 for every 1,000 hospital admissions. Further, the data shows that 13% of Veterans with seizures were less than 45 years old, 39% were between 45-65 years old, and about 8% were female. Having PTE significantly compromises a person's life since it excludes participation in day-to-day activities from driving to employment. Despite the development of newer generations of antiepileptic drugs, seizures remain uncontrolled in 30% of patients. Hence, there is an urgent need for the development of rationally designed therapeutic strategies capable of preventing epilepsy and its progression. To pursue our goal to utilize adenosine for the prevention of PTE, critical gaps in knowledge will be addressed in the following aims. I. Examine the distribution and role of ADK in PTE. This aim will focus on a specific form of ADK (ADK-L), which is expressed in the cell nucleus and determines how genes are expressed. This form of ADK has a specific function in epilepsy development and its distribution after brain injury in mice will be studied here. This is a novel and game-changing approach for the development of targeted treatment options. II. Investigate changes in the activity of neurons linked to TBI and ADK. This aim, in line with the mechanistic vision of the Epilepsy Research Program, will use conventional electrophysiological tools to investigate the mechanistic roles of ADK isoforms, particularly ADK-L. This will enhance our understanding of how ADK-L and associated DNA methylation changes affect neuronal excitability and thereby, epilepsy development. III. Test ADK inhibitors for their potential to prevent epilepsy. We have a set of conventional, and more specific ADK inhibitors, which we will test in mice subjected to a controlled brain injury to trigger epilepsy. The drugs will be given only transiently for a period of 1 week, beginning 3 days after the injury, to prevent epilepsy development long term. Innovation of Research Approach: We have developed innovative research tools (transgenic mice and selective ADK inhibitors) to specifically test the function of nuclear ADK-L for epilepsy development. This approach will allow us to characterize and develop ADK-L as rational therapeutic target for epilepsy prevention. Impact and Translational Significance: C