Lacosamide treatment following status epilepticus attenuates neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model

Abstract

and †CNS Research, UCB Pharma, Braine L'Alleud, Belgium SUMMARY Purpose: The antiepileptic drug, lacosamide, exerts its therapeutic activity by enhancing slow inactivation of voltage-gated sodium channels. Because putative preventive or disease-modifying effects of drugs may affect epileptogenesis, intrinsic severity, and comorbidities, it is of particular interest to assess the effect of lacosamide on the development of epilepsy and associated cellular alterations. Methods: The effect of lacosamide was evaluated in an electrical rat status epilepticus (SE) model with a 24-day treatment phase following induction of SE. The impact of lacosamide on the development of spontaneous seizures based on continuous video-electroencephalography (EEG) monitoring, as well as the impact on neuronal cell loss and alterations in hippocampal neurogenesis, was assessed.Key Findings: Neither low-dose nor high-dose lacosamide affected the development of spontaneous seizures. A dose-dependent neuroprotective effect of lacosamide with significant reduction of neuronal cell loss was observed in the hippocampal CA1 region, as well as in the piriform cortex. In addition, lacosamide attenuated the impact of SE on the rate of hippocampal cell neurogenesis. Moreover, lacosamide prevented a significant rise in the number of persistent basal dendrites. Significance: Our data do not support an antiepileptogenic effect of lacosamide. However, because lacosamide reduced SE-associated cellular alterations, it would be of interest to determine whether these effects indicate a putative disease-modifying effect of lacosamide in future studies.

Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy

“…C. Rates of interictal spikes from day 4 to day 14 after SE in controls and in LCM-treated animals, in CA3 and subiculum (* p < 0.05, ** p < 0.01) (vertical dotted lines define the peak of seizure occurrence in control animals). study found a neuroprotective effect of LCM on hippocampal and parahippocampal structures when administered after a SE induced with prolonged stimulation of the basolateral amygdala, without however any effect on the duration of the latent period (Licko et al, 2013). Although the methods used to monitor seizures are different between the study of Licko et al (2013) and our study, these results highlight the need for additional studies addressing the potential disease-modifying properties of LCM.…”

Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide

“…Furthermore, histological analysis revealed no difference in the extent of neurodegeneration, axonal injury, or hilar neuron loss within the hippocampus of lacosamide-treated rats compared to vehicle treatment. Recently, Licko and colleagues sought to expand previous reports on the anti-epileptogenic potential of lacosamide following status epilepticus [81]. To avoid any possible interference with the induction of sustained SE, lacosamide treatment began following its cessation and was continued for 23 days.…”

“…Despite the impact on molecular changes induced by SE and contrary to previous reports, lacosamide treatment did not successfully prevent the development of SRS. Additionally, latency to first seizure and the frequency of spontaneous seizures were not attenuated by chronic lacosamide treatment [81]. While the treatment paradigm was somewhat unorthodox, combining oral administration and continuous infusion via osmotic minipump, it is unlikely that this would account for the lack of efficacy in preventing the development of spontaneous seizures.…”

Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury

“…Furthermore, (S)-LCM is unlikely to affect hippocampal cell death as a recent study demonstrated that the parent compound (R)-LCM does not alter neuronal survival following TBI (Pitkanen et al, 2014). The lack of significant separation between (S) -LCM- and vehicle-treated groups may be a result of the nature of administration, despite the previous success observed with infusion of (R) -LCM in a separate study (Licko et al, 2013). While continuous subcutaneous infusion was considered to be preferable over daily intraperitoneal injections, it is possible that inflammation at the implantation site may have been a factor.…”