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Protection against dendrotoxin-induced clonic seizures in mice by anticonvulsant drugs
M H Coleman1, S Yamaguchi, M A Rogawski
1Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
Abstract:
Various anticonvulsant drugs were evaluated for their ability to protect against clonic seizures induced in mice by intraventricular injection of the K+ channel blocking peptide dendrotoxin (DTX). Phenytoin, the phenytoin-like anticonvulsant carbamazepine and the broad spectrum drug valproate were effective in this model, whereas the GABA-enhancers diazepam and tiagabine, the NMDA antagonists (+/-)-CPP and (+)-MK-801, the AMPA antagonist NBQX, the antiabsence drug ethosuximide and the Ca2+ channel antagonist nimodipine were inactive. In contrast to the lack of activity of other NMDA antagonists, phencyclidine and ADCI [(+/-)-aminocarbonyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine] were potent antagonists of DTX-induced seizures.
Insights
Certain anticonvulsant drugs like phenytoin, carbamazepine, and valproate effectively protected mice against seizures induced by dendrotoxin (DTX). However, other drug classes, including NMDA antagonists, were ineffective, highlighting specific therapeutic targets for DTX-induced epilepsy.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Dendrotoxin (DTX), a peptide that blocks K+ channels, is known to induce clonic seizures.
- Understanding the anticonvulsant drug profile against DTX-induced seizures is crucial for developing targeted epilepsy therapies.
Purpose of the Study:
- To evaluate the efficacy of various anticonvulsant drugs in a mouse model of DTX-induced seizures.
- To identify specific drug classes and mechanisms effective against K+ channel blocker-induced epilepsy.
Main Methods:
- Intraventricular injection of DTX in mice to induce clonic seizures.
- Administration and assessment of various anticonvulsant drugs, including phenytoin, carbamazepine, valproate, diazepam, tiagabine, NMDA antagonists, AMPA antagonists, ethosuximide, and nimodipine.
Main Results:
- Phenytoin, carbamazepine, and valproate demonstrated significant protection against DTX-induced seizures.
- GABA-enhancers, most NMDA antagonists (except phencyclidine and ADCI), AMPA antagonists, ethosuximide, and nimodipine were found to be inactive in this seizure model.
- Phencyclidine and ADCI showed potent antagonism of DTX-induced seizures, contrasting with other NMDA antagonists.
Conclusions:
- The study identifies specific anticonvulsant drugs effective against DTX-induced seizures, suggesting a particular mechanism of action.
- Results indicate that drugs targeting K+ channels or specific NMDA receptor subtypes may be more effective for this type of seizure.
- This research provides valuable insights into the neuropharmacology of DTX-induced seizures and potential therapeutic strategies.