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Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug.

Abstract
In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available antiepileptic drugs target voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that eslicarbazepine acetate, a once-daily antiepileptic drug, may constitute a candidate compound that addresses both issues. Eslicarbazepine acetate is converted extensively to eslicarbazepine after oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if eslicarbazepine, the major active metabolite of eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental epilepsy with significant add-on effects to carbamazepine in human epilepsy. Second, we show that eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of epilepsy in mice has an effect on the development of chronic seizures and neuropathological correlates of chronic epilepsy. We found that eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental epilepsy. EEG monitoring showed that transitory eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover, eslicarbazepine acetate treatment resulted in a significant decrease in mossy fibre sprouting into the inner molecular layer of pilocarpine-injected mice, as detected by Timm staining. In addition, epileptic animals treated with 150 mg/kg, but not those that received 300 mg/kg eslicarbazepine acetate showed an attenuated neuronal loss. These results indicate that eslicarbazepine potentially overcomes a cellular resistance mechanism to conventional antiepileptic drugs and at the same time constitutes a potent antiepileptogenic agent.
AuthorsAnna Doeser, Gesa Dickhof, Margit Reitze, Mischa Uebachs, Christina Schaub, Nuno Miguel Pires, Maria João Bonifácio, Patrício Soares-da-Silva, Heinz Beck
JournalBrain : a journal of neurology (Brain) Vol. 138 Issue Pt 2 Pg. 371-87 (Feb 2015) ISSN: 1460-2156 [Electronic] England
PMID25472797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].
Chemical References
  • Anticonvulsants
  • Convulsants
  • Dibenzazepines
  • Pilocarpine
  • eslicarbazepine acetate
  • Scopolamine
Topics
  • Adolescent
  • Adult
  • Animals
  • Anticonvulsants (pharmacokinetics, therapeutic use)
  • CHO Cells
  • Child
  • Child, Preschool
  • Convulsants
  • Cricetulus
  • Dibenzazepines (pharmacokinetics, therapeutic use)
  • Epilepsy (chemically induced, drug therapy, physiopathology)
  • Hippocampus (drug effects)
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Middle Aged
  • Pilocarpine
  • Postural Balance (drug effects)
  • Rats
  • Rats, Wistar
  • Scopolamine
  • Young Adult

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