The P2X7 receptor as treatment target for traumatic brain injury-induced epilepsy

Objetivo

Post-traumatic epilepsy (PTE) is one of the most common, devastating complications following traumatic brain injury (TBI), and is particularly prone to drug-refractoriness. Critically, current anti-seizure medication remains ineffective in over 30% of patients, with no impact on disease progression and frequent adverse side effects. Increasing evidence suggests inflammation as one of the main contributors to the development of PTE. ATP, released during pathological processes in the brain, functions as an important extracellular signalling molecule driving inflammatory processes via the activation of the ATP-gated ionotropic P2X7 receptor (P2X7R). Increasing evidence suggests that targeting of the P2X7R provides potent anticonvulsive effects and, possibly, disease-modification during epilepsy. Whether P2X7R antagonism prevents the development of PTE has not been investigated to date. My planned research will 1) investigate the disease-modifying potential of targeting the ATP-gated P2X7R on TBI-induced epilepsy and associated comorbidities, thereby sparing patients from life-long drug dependency, and 2) evaluate the potential of P2X7R-based PET imaging as novel patient stratification tools to identify patients at risk of developing PTE for an earlier and more effective treatment start. EpiPrevent brings together a team of experts in purinergic signalling, industrial partners developing novel P2X7R antagonists and clinicians specialised in epilepsy. This highly interdisciplinary and intersectoral approach will add a significant contribution to the understanding of purinergic signalling during TBI, providing novel diagnostic and therapeutic approaches. The skills acquired during the research project, the excellent training record of the supervisor and host institution and the outstanding resources for learning and development available at RCSI will give me the tools necessary to establish myself as independent scientist.