title: Inflammation in epileptogenesis after traumatic brain injury.
abstract: Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.
  
  
  
  Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia.
authors.forename: Kyria M
authors.initials: KM
authors.lastname: Webster
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia.
authors.forename: Mujun
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Crack
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Shultz
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia. Bridgette.Semple@unimelb.edu.au.
authors.forename: Bridgette D
authors.initials: BD
authors.lastname: Semple
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000453:epidemiology / Q000276:immunology* / Q000378:metabolism*; D004198:Disease Susceptibility / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism; D004827:Epilepsy / Q000453:epidemiology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism; D012640:Seizures / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
keywords: Astrocytes; Cytokine; Epilepsy; Inflammation; Interleukin; Post-traumatic epilepsy; Seizures; Traumatic brain injury