Treatment of early and late kainic acid‐induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466

Abstract

Summary Purpose Benzodiazepines such as diazepam may fail to effectively treat status epilepticus because benzodiazepine-sensitive GABAA receptors are progressively internalized with continued seizure activity. Ionotropic glutamate receptors, including AMPA receptors, are externalized, so that AMPA receptor antagonists, which are broadspectrum anticonvulsants, could be more effective treatments for status epilepticus. We assessed the ability of the noncompetitive AMPA receptor antagonist GYKI 52466 to protect against kainic acid–induced status epilepticus in mice. Methods Groups of animals treated with kainic acid received GYKI 52466 (50 mg/kg followed in 15 min by 50 mg/kg) or diazepam (25 mg/kg followed in 20 min by 12.5 mg/kg) beginning at 5 min of continuous seizure activity or 25 min later. The duration of seizure activity was determined by EEG recording from epidural cortical electrodes. Results Both GYKI 52466 and diazepam rapidly terminated electrographic and behavioral seizures when administered early. However, diazepam-treated animals exhibited more seizure recurrences. With late administration, GYKI 52466 also rapidly terminated seizures and they seldom recurred, whereas diazepam was slow to produce seizure control and recurrences were common. Although both treatments caused sedation, GYKI 52466-treated animals retained neurological responsiveness whereas diazepam-treated animals did not. GYKI 52466 did not affect blood pressure whereas diazepam caused a sustained drop in mean arterial pressure. Discussion Noncompetitive AMPA receptor antagonists represent a promising approach for early treatment of status epilepticus; they may also be effective at later times when there is refractoriness to benzodiazepines.

Combined treatment with diazepam and allopregnanolone reverses tetramethylenedisulfotetramine (TETS)-induced calcium dysregulation in cultured neurons and protects TETS-intoxicated mice against lethal seizures

“…Hypotension represents a key challenge in the use of benzodiazepines in the treatment of status epilepticus (Treiman et al, 1998; Fritsch et al, 2010). Accordingly, we sought to assess the impact of the combination treatment on blood pressure.…”

Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration

“…Status epilepticus will spontaneously remit after 5-6 h after pilocarpine or kainic acid administration (Curia et al, 2008;Fritsch et al, 2010). However, in order to reduce inter-animal variability, mortality rates as well as to design specific experimental protocols, the status epilepticus can be stopped in both models after 30-120 min by concomitant administration of ketamine (50 mg/kg i.p or s.c.) and diazepam (20 mg/kg i.p or s.c.) (Martin and Kapur, 2008;Vermoesen et al, 2010).…”

Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus

“…Furthermore, the benzodiazepine-refractory SE in experimental animals can be terminated by attenuating the fast excitatory transmission mediated by AMPAR (Fritsch et al, 2010; Pitk+ñnen et al, 2007;Rajasekaran et al, 2012; Hanada et al, 2014). However, it is unknown whether AMPAR-mediated transmission is enhanced during SE and the mechanisms that cause this enhancement are unclear.…”