Post-traumatic epilepsy (PTE) is one of the most common and devastating complications of traumatic brain injury (TBI) with a variety of consequences for patient care, recovery, and outcomes (TBI) . PTE is defined two or more unprovoked seizures more than a week after injury [1,2,3]. A unique feature of these unprovoked (occurring 7 < days post TBI), recurrent seizures is the latency; they may initially occur from weeks to years after TBI, typically occurring within 5 years of the head injury [1, 4, 5]. Latency up to 20 years has been described in literature . The development of PTE after TBI varies with type and prevalence but may be as high as 50% [1, 5]. Those at greatest risk are those with penetrating, versus closed head, injury and is directly correlated to injury severity [1, 6]. Many of those studied are veterans as they represent a significant population at risk for TBI, and the impact on quality of life can be significant . Changes in behavior can result from seizures and result in incorrectly treatment due to symptom overlap with post-traumatic stress disorder . Seizures also represent a physical danger to health, as accidents, injury and aspiration can happen during seizure; furthermore, in one population, reoccurrence of epileptic seizures within the next 2 years in TBI patients with a single acute post-traumatic seizure (PTS) was as high 86%, suggesting the risk of developing PTE after PTS is extremely high possibly due to alterations in inter-neuronal connections, increasing future susceptibility . Many may also suffer silent, non-convulsive seizures [1, 2]. Sudden death may also occur in uncontrolled seizures possibly due to alterations in blood pressure, heart rate, hyperthermia or hypoxemia . There remains stigma surrounding those with epilepsy, and those with uncontrolled seizures are prevented from driving and may have difficulty attaining and/or maintaining gainful employment, further challenging the re-integration into society that veterans with TBI face .
Though its myriad of consequences, there are no current treatments specific to PTE [1, 2, 8]. Development of new therapeutic targets is imperative because modern treatment of PTE is aimed at controlling seizures with antiepileptic drugs; although, up to 30% of those with PTE are medication resistant and their efficacy in prophylaxis is disputed [2, 8]. Of significance, one study showed that none of the drugs used for seizure prophylaxis demonstrated prevented or even suppressed epileptic seizures after TBI . This is possibly due to differing underlying mechanisms between provoked seizures, which antiepileptic drugs have been demonstrated to help, and the unprovoked seizures that characterize PTE. Many studies have proceeded to propose hypotheses that attempt to explain why seizures occur post-TBI, but the lack of robust evidence has continued to make therapeutic target development challenging.
Despite the absence of a definitive mechanism, astrocytes appear to play a role in the development of PTE [9,10,11,12,13,14]. Astrocytes are a specific type of glial cell in the central nervous system that preserve neural circuit function through the maintenance of neuronal homeostasis . Astrocytes play an integral role in the response to a variety of neuronal insults through reactive astrogliosis—characterized by cellular hypertrophy, astrocyte proliferation, and increased glial fibrillary acidic protein (GFAP) expression—and the resulting formation of a glial scar to protect healthy cells from harmful substances [12, 14, 15]. This glial scar may be directly epileptogenic, or it may be indirectly epileptogenic—through the downstream actions of cytokines on astrocytes [11, 13,14,15,16,17]. Therefore, understanding of the specific cell-signaling pathways involved may allow for the development of future therapeutic regimens. As previous literature has examined the role of reactive gliosis in epileptogenesis [10, 11, 14], the role of the c-Jun N-terminal kinase (JNK) signaling in reactive gliosis , and the activation of the JNK signaling pathway by glutamate [18,19,20], we sought to examine the relationship between reactive gliosis and the JNK cell-signaling pathway in the development of PTE in an animal model.