Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Area of Science:

• Neuroscience
• Pharmacology
• Epileptology

Background:

• Epilepsy affects 15-20% of individuals following acute central nervous system (CNS) insults like traumatic brain injury (TBI) and cerebrovascular accidents (CVA).
• A critical latency period exists between CNS injury and epilepsy development, offering a window for preventive interventions.
• Currently, no established treatments exist to prevent or modify post-injury epilepsy.

Purpose of the Study:

• To review existing animal and human evidence for the antiepileptogenic potential of repurposed medications.
• To identify knowledge gaps hindering clinical translation of these promising therapies.
• To propose a standardized platform for evaluating potentially repurposable antiepileptogenic molecules.

Main Methods:

• Comprehensive review of preclinical (animal models) and clinical (human) studies on medications with antiepileptogenic effects.
• Analysis of data heterogeneity across studies, including injury models, dosing, treatment timing, and outcome measures.
• Identification of essential data requirements for clinical translation, such as dose-blood level relationships and target engagement.

Main Results:

• Numerous medications, including atorvastatin, ceftriaxone, losartan, and several antiseizure drugs, demonstrate antiepileptogenic effects in animal models.
• Significant heterogeneity in preclinical study designs impedes direct comparison and selection of candidates for clinical trials.
• Most studies lack critical translational data, such as dose-response relationships and brain target engagement.

Conclusions:

• Repurposable medications offer a potential avenue for epilepsy prevention, but significant research gaps must be addressed.
• Standardized preclinical evaluation platforms are necessary to facilitate the clinical translation of antiepileptogenic therapies.
• Further research is needed to bridge the gap between preclinical findings and effective clinical strategies for preventing post-injury epilepsy.