Inflammation in epileptogenesis after traumatic brain injury

Abstract

BackgroundEpilepsy 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.BodyWe 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.ConclusionSeveral 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.

Age‐dependent release of high‐mobility group box protein‐1 and cellular neuroinflammation after traumatic brain injury in mice

“…There was also an early and robust increase in serum HMGB1 by 2 hr postinjury. After TBI in the adult brain, there was also an increase in astrocytes and microglia/macrophage reactivity relative to their sham controls, albeit not as robust in magnitude as the response in pediatric mice, and this cellular inflammatory response was delayed in onset to 3 days postinjury, consistent with other studies in adult animals (Kreutzberg, ; Webster et al, ). Although there was no increase in serum HMGB1 in the adult injured brain, we did observe localized extracellular release of HMGB1 in the injured neocortex at 3 days after TBI.…”

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

“…IL‐1 is a family of pro‐inflammatory cytokines and mediates innate immune response and IL‐1β from the family is the one extensively investigated against epilepsy (Webster et al . ). The impact of IL‐1R/TLR signaling in epileptogenesis, characterized by neuronal hyperexcitability which might be provoked by IL‐1β and HMGB1 provides insight into how IL‐1R/TLR4 signaling might contribute in seizure generation after induction of inflammatory cascades (Iori et al .…”

“…neurobehavioral and neuropsychiatric disorders, with significant consequences for patients, their families, and society (Yang et al 2017). But much remains to be elucidated about the precise mechanisms of epileptogenesishowever, a plethora of findings over the past decade have highlighted the crucial pathophysiological role of brain inflammation in epilepsy Webster et al 2017;Paudel et al 2018b).…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…8,9 There is evidence supporting a reciprocal causal link between neuroinflammation and epilepsy. 4,[10][11][12] Experimental findings have highlighted that seizure activity is sufficient per se to trigger synthesis and release of pro-inflammatory molecules from brain resident cells. This event is part of a phenomenon defined "neurogenic inflammation."…”