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BICS01 Mediates Reversible Anti-seizure Effects in Brain Slice Models of Epilepsy - PubMed

  • ️Sat Jan 01 2022

BICS01 Mediates Reversible Anti-seizure Effects in Brain Slice Models of Epilepsy

Gareth Morris et al. Front Neurol. 2022.

Abstract

Drug-resistant epilepsy remains a significant clinical and societal burden, with one third of people with epilepsy continuing to experience seizures despite the availability of around 30 anti-seizure drugs (ASDs). Further, ASDs often have substantial adverse effects, including impacts on learning and memory. Therefore, it is important to develop new ASDs, which may be more potent or better tolerated. Here, we report the preliminary preclinical evaluation of BICS01, a synthetic product based on a natural compound, as a potential ASD. To model seizure-like activity in vitro, we prepared hippocampal slices from adult male Sprague Dawley rats, and elicited epileptiform bursting using high extracellular potassium. BICS01 (200 μM) rapidly and reversibly reduced the frequency of epileptiform bursting but did not change broad measures of network excitability or affect short-term synaptic facilitation. BICS01 was well tolerated following systemic injection at up to 1,000 mg/kg. However, we did not observe any protective effect of systemic BICS01 injection against acute seizures evoked by pentylenetetrazol. These results indicate that BICS01 is able to acutely reduce epileptiform activity in hippocampal networks. Further preclinical development studies to enhance pharmacokinetics and accumulation in the brain, as well as studies to understand the mechanism of action, are now required.

Keywords: anti-seizure drugs; drug therapy; epilepsy; epileptiform activity; seizure.

Copyright © 2022 Morris, Heiland, Lamottke, Guan, Hill, Zhou, Zhu, Schorge and Henshall.

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Conflict of interest statement

BICS01 was developed by Bicoll GmbH. KL is a full-time employee of Bicoll GmbH and HG, YZ, and QZ are full-time employees of Bicoll Biotechnology (Shanghai) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

BICS01 reduces epileptiform bursting in hippocampal slices treated with 9 mM K+. (A) Representative trace showing epileptiform bursting in hippocampal CA1 elicited by 9 mM K+, before (i), during (ii) and after (iii) application of 200 μM BICS01. Raster plot shows instantaneous burst frequency throughout the experiment. (B) Summary data shows a significant decrease in burst frequency in the presence of 200 μM BICS01, which is reversed upon washout (RM one-way ANOVA with Dunnet's post hoc tests; p values marked on graph). Changes in burst amplitude caused by 200 μM BICS01 were not consistent between slices. (C) Stimulus-response curves and (D) paired-pulse facilitation are not altered by BICS01 (*truncated stimulus artifact, and amplitude of traces in (D) normalized to response to the first pulse). (E) 200 μM BICS01 mediates a stronger reduction in epileptiform bursting then 30 μM carbamazepine [CBZ data from (12)].

Figure 2
Figure 2

Acute systemic application of BICS01 has limited effects in an acute in vivo seizure model. (A) Experimental overview. BICS01 (100, 300, or 1,000 mg/kg) or 0.9% NaCl vehicle were administered via IP injection 30 min prior to acute seizure induction with pentylenetetrazol. Mice were video monitored for the following 30 min to observe the behavioral manifestation of acute seizures. (B) Latencies to atypical seizure, myoclonic jerk and tonic-clonic seizure, as well as maximum seizure severity reached, were all unchanged.

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References

    1. Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: A systematic review and meta-analysis. Neurology. (2011) 77:1005–12. 10.1212/WNL.0b013e31822cfc90 - DOI - PMC - PubMed
    1. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. (2020) 72:606–38. 10.1124/pr.120.019539 - DOI - PMC - PubMed
    1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study. JAMA Neurol. (2018) 75:279–86. 10.1001/jamaneurol.2017.3949 - DOI - PMC - PubMed
    1. Schmidt D, Löscher W. Drug resistance in epilepsy: Putative neurobiologic and clinical mechanisms. Epilepsia. (2005) 46:858–77. 10.1111/j.1528-1167.2005.54904.x - DOI - PubMed
    1. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. (2012) 11:792–802. 10.1016/S1474-4422(12)70153-9 - DOI - PubMed

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