Lestaurtnib (CEP-701) as a Neuroprotective Treatment for Convulsive Status Epilepticus in a Peri-adolescent Rat Model: An Electrophysiological and Behavioral Study

Abstract

Introduction: Convulsive Status Epilepticus (CSE) is the most common pediatric nonsurgical neurological emergency. CSE as a result of temporal lobe epilepsy is associated with various chronic cognitive and psychiatric impairments in children with several severities. However, there are no drugs currently available to prevent these detrimental behavioral deficits seen both in the clinic and in animal models. Hence, there is a desperate need to devise novel neuroprotective strategies. In our laboratory, we have discovered that Lestaurtinib (CEP-701), an FDA-approved drug in cancer research, can alter the duration of CSE in a peri-adolescent rat model of kainic acid (K.A.)-induced seizures1. We aim at investigating the neuroprotective effects of CEP-701 against known detrimental behavioral epilepsy of temporal lobe origin. Under EEG monitoring, CSE was induced with amygdalar K.A. (LKV &LKCEP groups) while controls get saline (LSV &LSCEP groups) at post-natal day 40 (P40). CEP701(15mg/kg) or its vehicle (DMSO) were then administered intraperitoneally 15 minutes post-CSE onset. CSE was terminated after 3 hours with diazepam. Our behavioral tests included a full panel of tests to assess for depressive-like and anxietylike and cognitive behaviors. We conducted a long-term continuous EEG monitoring for 30 days to check for latent spontaneous seizure recurrence. Finally, rats were sacrificed at postnatal day 100 (P100) and their hippocampi were assessed for neuronal damage, using NeuN and GFAP immunohistochemistry staining respectively. Results: In this study, all rats that got the K.A had seizures of equal latency to onset and duration which were all uniformly terminated after the administration of diazepam (P > 0.05). At post behavioral stage of the study (P70-P100) all LKV groups had spontaneous recurrent seizures (SRS) (P > 0.05), unlike the LKCEP where we observed the tendency of the treatment to prevent SRS. Our preliminary behavioral data in the Morris-watermaze, forced-swim and open-field tests showed that the injured group had a contextual learning deficit when compared to the controls. Also, the treated group had a lesser deficit in the open field and forced swim test compared to the injured, however, the results were statistically comparable. All other tests were comparable among the groups. The initial results from the histological assays also showed more neuronal loss in the hippocampi of 2the injured groups (LKV) compared to the control (LSV) but were comparable to the treated group (LKCEP). While we can see from our preliminary long-term EEG assessment that the injured untreated group (LKV) had spontaneous recurrent seizures unlike the treated groups (LKCEP). Conclusion: Here we show, the potential anti-epileptogenesis properties of CEP-701 and its tendency to improve the behavioral outcome prevalently seen in TLE. Given its known safety in humans, neuroprotective evidence of CEP-701 against the CSE-induced laterlife sequelae as well as its effect on cognitive behaviors is a promising start for further research in order to repurpose it for CSE patients.