Epilepsy, a chronic neurological disorder affecting over 80 million people worldwide, poses significant health concerns. Approximately 30% of epilepsy cases are acquired, resulting from precipitating injuries such as traumatic brain injury (TBI). TBI is a leading cause of injury-related death and disability globally, with devastating consequences for patients and their families. Despite the development of over 30 anti-seizure medications (ASMs), approximately 30% of patients experience uncontrolled seizures.
The EpiPurines project aims to test the disease-modifying potential of targeting the purinergic system, specifically adenosine and ATP-gated P2X7 receptors. By using mouse models of epilepsy and combinatory pharmacological treatments, this project seeks to prevent or ameliorate epilepsy development, addressing a critical unresolved health concern with significant implications for improving quality of life for those affected.
Key Objectives:
Objective 1 (M1-12, RU): Determine the anti-epileptogenic properties of increased adenosine in a mouse model of TBI. In our first objective we will test whether adenosine-based treatment using highly specific ADK inhibitors prevents/ameliorates the development of epilepsy in a mouse model of post-traumatic epilepsy (Work package (WP) 1).
Outcome: this study showed that ADK and DNA methylation inhibitors are not efficient to prevent seizures in a mouse model of CCI-induced PTE. A possible limitation may be associated with the duration of the treatment, suggesting that these inhibitors do not present a long-lasting effect, requiring a longer treatment window to, eventually, present a reduction in spontaneous seizures in mice with PTE.
Objective 2 (M 13-24, RU): Evaluate the disease-modifying potential of a combinatory treatment based on the simultaneous targeting of the ATP-gated P2X7 receptor and ADK during epileptogenesis and epilepsy. In our second objective we will test whether simultaneous targeting of the ATP-gated P2X7 receptor and ADK will provide a synergistic effect in preventing the development of epilepsy and revert chronic epilepsy. To this end, we will use highly specific P2X7 agonists (provided by our collaborators Janssen R&D & Affectis) in combination with highly specific strategies to block ADK (e.g. inhibitors, ADK-targeting gene therapy vectors) (WP2).
Outcome: The results showed a small trend to reduce the number of HPDs in mice treated with 5-ITU-JNJ565 when compared with KA-veh mice, and a significant reduction in the number of HPDs when compared with the mice treated with JNJ565-5-ITU 4 weeks after KA injection.
