Diurnal burden of spontaneous seizures in early epileptogenesis in the post‐kainic acid rat model of epilepsy

Abstract

Epilepsy is a chronic neurological condition characterized by spontaneous recurrent seizures (SRS). SRS can occur more frequently during specific times of day or night in humans; 1-3 that is, some patients experience peak epileptiform activity at night or the late afternoon. 1,4 However, it is less clear to what extent rodent models of acquired temporal lobe epilepsy (TLE) also demonstrate similar SRS periodicity, especially in early epileptogenesis. Some studies have found an intrinsic SRS rhythm in various rodent TLE models, [5][6][7][8][9] whereas others have reported no circadian pattern. 10 Further, studies that have assessed SRS periodicity were often conducted with small cohorts or only monitored SRS for brief durations in fully established epilepsy. 6,7,[9][10][11] Monitoring well after epilepsy is established does not inform on the potential to mitigate disease severity through pharmacological intervention shortly after the inciting epileptogenic event. Most drug discovery programs for epilepsy currently focus on the effect of treatments on established SRS, 12 rather than on early metrics

Development of an antiepileptogenesis drug screening platform: Effects of everolimus and phenobarbital

“…First, SRS of the post‐KA SE rat model of TLE arise after a well‐defined and reliable latent period 7 . Second, the model reproduces the interindividual heterogeneity of SRS onset, severity, and frequency, 6 which may lead to a greater likelihood of successfully translating preclinical findings to clinical use. Third, the post‐KA SE rat model of TLE is characterized by SRS that are resistant to a number of ASDs 5,12,13 .…”

“…Spontaneous recurrent seizures (SRS) in clinical TLE are often focal impaired awareness seizures that generalize to tonic–clonic seizures and develop after a latent period following a neurological insult, including SE 5 . The rat systemic kainic acid (KA)‐induced SE model of TLE is a technically feasible and well‐characterized preclinical model that is defined by SRS onset within 0–2 weeks following a latent period 6–8 . Post‐KA SE rats exhibit marked reactive gliosis, 9 neuroinflammation, 10 and behavioral deficits 11 days to weeks after SE insult.…”

“…Post‐KA SE rats exhibit marked reactive gliosis, 9 neuroinflammation, 10 and behavioral deficits 11 days to weeks after SE insult. As a result of the pathophysiological and phenotypic similarities to clinical TLE, as well as the sensitivity of SRS to available ASDs in this model, 5,12,13 the KA‐induced SE paradigm in rats is well suited for moderate‐throughput drug discovery to screen the disease‐modifying potential of investigational agents on the development and severity of SRS 6,14 …”

“…As a result of the pathophysiological and phenotypic similarities to clinical TLE, as well as the sensitivity of SRS to available ASDs in this model, 5,12,13 the KA-induced SE paradigm in rats is well suited for moderatethroughput drug discovery to screen the disease-modifying potential of investigational agents on the development and severity of SRS. 6,14 This study aimed to establish and validate an in-life disease modification screen using the repeated administration of the ASD phenobarbital (PB) or the immunomodulator everolimus (EVL) to rats immediately following the induction of SE. The primary study objective was to rigorously evaluate the extent to which pharmacological intervention after SE induction would modify the severity and/or frequency of SRS up to 6 weeks later.…”

Continuous Seizure Emergency Evoked in Mice with Pharmacological, Electrographic, and Pathological Features Distinct from Status Epilepticus

“…24; 25 However, there is yet no predictable way to reliably produce cluster seizures in epilepsy models because of the high degree of interindividual variability. 26 It has been thus challenging to consistently reproduce all types of clinical seizure emergencies in preclinical models to help elucidate the pathophysiological processes that differentiate SE from seizure clusters.…”