In search of antiepileptogenic treatments for post-traumatic epilepsy

Abstract

Post-traumatic epilepsy (PTE) is diagnosed in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.

Keywords: Antiepileptogenesis; Disease modification; Inflammation; Iron; Neurodegeneration; Outcomes; Preclinical trial; Tau; Traumatic brain injury.

Fig. 1.

A TBI triggers the upregulation of a wide range of pro-inflammatory mediators and their signaling pathways. Many of these, including those noted here, have been implicated in the development of epilepsy based on observations in patient samples as well as experimental manipulations in small animal models. See text for further details and source citations. Abbreviations: COX-2 = cyclooxygenase-2, CX3CR1 = CX3C chemokine receptor 1, C5ar1 = complement component 5a receptor 1, HMGB1 = high mobility group box protein-1, IL-1β = interleukin-1 beta, IL-1R1 = interleukin-1 receptor 1, NFκB = nuclear factor kappa-B; PGE2 = prostaglandin E2, MAPK = p38 mitogen activated protein kinase, TGFβ = transforming growth factor beta, TLR4 = toll-like receptor 4, TNFα = tumor necrosis factor alpha, TNFR1 = tumor necrosis factor receptor 1.