Neuroinflammation in Post-Traumatic Epilepsy: Pathophysiology and Tractable Therapeutic Targets

Abstract

Epilepsy is a common chronic consequence of traumatic brain injury (TBI), contributing to increased morbidity and mortality for survivors. As post-traumatic epilepsy (PTE) is drug-resistant in at least one-third of patients, there is a clear need for novel therapeutic strategies to prevent epilepsy from developing after TBI, or to mitigate its severity. It has long been recognized that seizure activity is associated with a local immune response, characterized by the activation of microglia and astrocytes and the release of a plethora of pro-inflammatory cytokines and chemokines. More recently, increasing evidence also supports a causal role for neuroinflammation in seizure induction and propagation, acting both directly and indirectly on neurons to promote regional hyperexcitability. In this narrative review, we focus on key aspects of the neuroinflammatory response that have been implicated in epilepsy, with a particular focus on PTE. The contributions of glial cells, blood-derived leukocytes, and the blood-brain barrier will be explored, as well as pro- and anti-inflammatory mediators. While the neuroinflammatory response to TBI appears to be largely pro-epileptogenic, further research is needed to clearly demonstrate causal relationships. This research has the potential to unveil new drug targets for PTE, and identify immune-based biomarkers for improved epilepsy prediction.

Keywords: cytokines.; neuroinflammation; post-traumatic epilepsy; seizures; traumatic brain injury.

Figure 1

Temporal development of post-traumatic epilepsy (PTE). Traumatic brain injury (TBI) initiates a cascade of pathological processes including neuronal death and neuroinflammation, characterized by cytokine and chemokine upregulation (IL-1β, TNFα, IL-10 and CCL2), BBB dysfunction (endothelial cell disruption and red blood cell infiltration), activation of astrocytes and microglia, and infiltration of blood-derived leukocytes into the brain, including monocytes, macrophages, neutrophils and T-cells (please refer to Section 2 for further details on these factors). These processes may also influence chronic outcomes such as the development of PTE, which occurs across three phases. The first phase is the initial insult and the associated molecular and cellular mechanisms within the subsequent minutes to days. Next is a latency period (days to years after the primary injury). During this time, injury-induced neurogenesis and neuroplasticity contribute to repair and regrowth, while simultaneously, ongoing secondary injury processes promote neurodegeneration. Neuroinflammation is a key player in this response, and is thought to facilitate hyperexcitability in the brain which may ultimately result in spontaneous, recurrent seizures characteristic of PTE.