Document Detail


The anticonvulsant retigabine potently suppresses epileptiform discharges in the low Ca ++ and low Mg++ model in the hippocampal slice preparation.
MedLine Citation:
PMID:  10604606     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester, D-23129) is a broad acting anticonvulsant currently undergoing phase II clinical trials. An opening effect on leakage conductance K+ channels, potentiation of GABA induced currents and a weak blocking effect on Na+ and Ca++ channels were previously reported. The goal of this study was to investigate whether retigabine is capable of blocking epileptiform discharges in the low Ca++ and low Mg++ model in the hippocampal slice preparations and whether the anti-burst activity can be related to the K+ channel opening effect. In the low Ca++ model, synaptic transmission is blocked and discharges evolve from ephaptically-coupled neurons. Compounds which directly interfere with the threshold for action potential induction via alteration of ion channel function (i.e. Na+ channel blocker) may alter the discharges, while compounds interfering with synaptic transmission are not active. Retigabine suppressed the discharges in a concentration-dependent manner. A significant reduction in frequency without effect on amplitude was observed after application of 1 microM, and a full block of all discharges after application of 25 microM. The opener of the ATP sensitive K+ channels cromakalim was also active. Application of 300 microM cromakalim yielded to a lower frequency with no effects on the amplitude of discharges. Treatment with phenytoin and carbamazepine resulted in a marked reduction in amplitude accompanied by a rise in frequency; only at higher concentrations was a full block observed. The effect of retigabine therefore differs from sodium channel blockers and can be related to the K+ channel opening effect. In the low Mg++ model, excitatory neurotransmission is augmented by reducing the Mg++ block of NMDA channels. This results in development of interictal-like epileptiform activity in area CA1 in isolated hippocampal slices. Treatment with retigabine 10 microM resulted in a significant reduction of the discharges, and discharges were fully blocked after application of 25 microM. Qualitatively similar effects were observed with cromakalim and valproate, albeit at higher concentrations. The data indicate that retigabine exerts potent broad spectrum activity making it an interesting candidate for treatment of drug resistant patients.
Authors:
R Dost; C Rundfeldt
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Epilepsy research     Volume:  38     ISSN:  0920-1211     ISO Abbreviation:  Epilepsy Res.     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-01-24     Completed Date:  2000-01-24     Revised Date:  2013-05-01    
Medline Journal Info:
Nlm Unique ID:  8703089     Medline TA:  Epilepsy Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  53-66     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Arzneimittelwerk Dresden GmbH, Corporate R&D, ASTA Medica Group, Radebeul, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticonvulsants / pharmacology*
Calcium / deficiency*
Carbamates / pharmacology*
Electrophysiology
Epilepsy / physiopathology*
Hippocampus / physiopathology*
Magnesium Deficiency / physiopathology*
Male
Phenylenediamines / pharmacology*
Potassium Channels / agonists
Rats
Rats, Wistar
gamma-Aminobutyric Acid / physiology
Chemical
Reg. No./Substance:
0/Anticonvulsants; 0/Carbamates; 0/Phenylenediamines; 0/Potassium Channels; 12G01I6BBU/ezogabine; 56-12-2/gamma-Aminobutyric Acid; 7440-70-2/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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