Shun Ichi Yamaguchi

Effects of anticonvulsant drugs on 4-aminopyridine-induced seizures in mice

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.

Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models

The anticonvulsant activities of a noncompetitive (GYKI 52466) and a competitive (NBQX) AMPA/kainate antagonist were compared in the maximal electroshock (MES) seizure test and various chemoconvulsant models. Both antagonists were protective in the MES and pentylenetetrazol tests. GYKI 52466 was also protective against seizures and lethality induced by 4-aminopyridine, kainate and AMPA, but not by NMDA, whereas NBQX was ineffective in these chemoconvulsant tests. Both GYKI 52466 and NBQX produced motor impairment at doses similar to those that were protective in the MES test. Under some circumstances, noncompetitive AMPA/kainate antagonists could offer advantages over competitive antagonists in seizure therapy. However, neurological toxicity is an obstacle to the potential clinical use of both classes of agents.

Convulsant actions of the neurosteroid pregnenolone sulfate in mice

Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) receptor-mediated inhibitory responses and potentiate NMDA receptor-mediated excitatory responses in vitro. To assess the actions of the steroid as a modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, severe forelimb and hindlimb clonus, opisthotonos and explosive running. The seizures increased in severity and frequency with time and eventually progressed to status epilepticus, tonic hindlimb extension and death. The doses producing convulsions in 50% (CD(50)) and 97% (CD(97)) of animals were 92 and 205 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly increased the convulsant potencies of systemically administered pentylenetetrazol (30-50 mg/kg) and NMDA (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsant potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol)-induced seizures and lethality was conferred by the GABA(A) receptor positive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominantly via its effects on GABA(A) receptors, and also possibly by effects on NMDA receptors.

Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα

Abstract The scorpion venom peptide toxins tityustoxin-K α (TsTx-K α ) and pandinustoxin-K α (PiTx-K α ) are novel, highly potent and selective blockers of voltage-activated K + channels. PiTx-K α preferentially blocks rapidly inactivating (A-type) K + channels whereas TsTx-K α is selective for slowly inactivating (delayed rectifier-type) channels. K + channel blockers are known to induce seizures, but the specific K + channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K + channel type-specific scorpion toxins and the selective K + channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K + channels, and paxilline, a selective blocker of large conductance (maxi K) Ca 2+ -activated K + channels. Intracerebroventricular injection of recombinant TsTx-K α and PiTx-K α in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity ( status epilepticus ), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD 50 ) for TsTx-K α and PiTx-K α were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD 50 , 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 μg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin-induced seizures, but the NMDA receptor antagonists ( R )-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K + channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca 2+ -activated K + channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

Protection against dendrotoxin-induced clonic seizures in mice by anticonvulsant drugs

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.