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Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice
1Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Abstract:
The K+ channel blocker 4-aminopyridine (4-AP) causes epileptiform activity in in vitro preparations and is a potent convulsant in animals and man. In mice, 4-AP produces behavioral activation, clonic limb movements and wild running, followed by tonic hindlimb extension and death (ED97, 13.3 mg/kg, s.c.). We evaluated the ability of a series of anticonvulsant drugs to protect against 4-AP-induced seizures using lethality as the endpoint. Drugs with a phenytoin-like profile of activity were protective with ED50 values (all in mg/kg, i.p.) of 34.4 for phenytoin, 18.6 for carbamazepine, 26.9 for felbamate, and 41.5 for zonisamide. Phenobarbital and valproate also protected against 4-AP-induced seizures and lethality (ED50s, 30.6 and 301, respectively). In contrast the NMDA antagonists (+/-)-CPP and (+)-MK-801 were inactive as were the GABA enhancers diazepam, vigabatrin and tiagabine; the antiabsence drug ethosuximide; and the L-type Ca2+ channel blocker nimodipine. We conclude that drugs like phenytoin which block seizure spread are effective antagonists of seizures induced by K+ channel blockade. Drugs with specific actions on other cellular targets may be weak or inactive, presumably because they are unable to attenuate the spread of intense (non-NMDA receptor mediated) excitation evoked by 4-AP.
Insights
The K+ channel blocker 4-aminopyridine (4-AP) induces seizures. Phenytoin-like drugs effectively protected against 4-AP-induced seizures, suggesting they block seizure spread.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- 4-aminopyridine (4-AP) is a potassium channel blocker known to induce epileptiform activity and seizures.
- 4-AP causes behavioral activation, clonic movements, and potentially fatal tonic hindlimb extension in mice.
Purpose of the Study:
- To evaluate the anticonvulsant efficacy of various drugs against 4-AP-induced seizures in mice.
- To determine which drug classes are effective in mitigating seizures caused by K+ channel blockade.
Main Methods:
- Mice were administered 4-AP to induce seizures, with lethality serving as the primary endpoint.
- A series of anticonvulsant drugs were tested for their protective effects against 4-AP-induced mortality.
- ED50 values were calculated for protective drugs.
Main Results:
- Phenytoin, carbamazepine, felbamate, and zonisamide demonstrated significant protection against 4-AP-induced seizures.
- Phenobarbital and valproate also exhibited protective effects.
- NMDA antagonists, GABA enhancers, an antiabsence drug, and an L-type Ca2+ channel blocker were ineffective.
Conclusions:
- Anticonvulsant drugs that block seizure spread, such as phenytoin, are effective against seizures induced by K+ channel blockade.
- Drugs targeting other cellular mechanisms may be ineffective due to their inability to counteract the intense excitation caused by 4-AP.