Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam

Abstract

Tetramethylenedisulfotetramine (TETS), a noncompetitive GABAA receptor antagonist, is a potent, highly lethal convulsant that is considered to be a chemical threat agent. Here, we assessed the ability of the AMPA receptor antagonist perampanel to protect against TETS-induced seizures and lethality in mice when administered before or after treatment with the toxicant. For comparison, we conducted parallel testing with diazepam, which is a first-line treatment for chemically induced seizures in humans. Pre-treatment of mice with either perampanel (1–4 mg/kg, i.p.) or diazepam (1–5 mg/kg, i.p.) conferred protection in a dose-dependent fashion against tonic seizures and lethality following a dose of TETS (0.2 mg/kg, i.p.) that rapidly induces seizures and death. The ED50 values for protection against mortality were 1.6 mg/kg for perampanel and 2.1 mg/kg for diazepam. Clonic seizures were unaffected by perampanel and only prevented in a minority of animals by high-dose diazepam. Neither treatment prevented myoclonic body twitches. Perampanel and diazepam also conferred protection against tonic seizures and lethality when administered 15 min following a 0.14 mg/kg, i.p., dose of TETS and 5 min following a 0.2 mg/kg, i.p., dose of TETS. Both posttreatments were highly potent at reducing tonic seizures and lethality in animals exposed to the lower dose of TETS whereas greater doses of both treatments were required in animals exposed to the larger dose of TETS. Neither treatment was as effective suppressing clonic seizures. In an experiment where 0.4 mg/kg TETS was administered by oral gavage and the treatment drugs were administered 5 min later, perampanel only partially protected against lethality whereas diazepam produced nearly complete protection. We conclude that perampanel and diazepam protect against TETS-induced tonic seizures and lethality but have less impact on clonic seizures. Both drugs could have utility in the treatment of TETS intoxication but neither eliminates all seizure activity.

Neuroprotective Effect of Brivaracetam and Perampanel Combination on Electrographic Seizures and Behavior Anomalies in Pentylenetetrazole-Kindled Mice

“…Perampanel, available as a triturate tablet, named Fycompa (Eisai. Co. Ltd., Japan) was solubilized in 1% tween to use its dose of 0.25 mg/kg . Diazepam, available as a commercial formulation named Valium, from Roche Pharma was diluted in distilled water, and its dose of 1 mg/kg was used …”

Effects of the AMPAr antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload

“…Brains were quickly dissected and hippocampi were isolated and stored at -80ºC for subsequent RT-qPCR. The dose of PER was chosen based on previous animal studies [21,22].…”

In the fast lane: Receptor trafficking during status epilepticus

“… 393 Perampanel, a noncompetitive AMPAR blocker, similarly has had anecdotal success with treatment of SE 394 , 395 , 396 and with the reduction of some seizure types in animal models of extreme SE. 397 However, conducting these clinicals trials is a difficult feat, and a recent clinical trial for treatment of refractory SE that compared ketamine infusion to traditional general anesthetic agents that target GABA‐ARs (KETASER01) was recently withdrawn because of eligibility requirments and unsuccessful recruitment. 398 Other clinical trails of ketamine with different study designs currently are underway.…”

“…NMDAR blockaded by ketamine for treatment of SE has been reported to have a clinical success rate as high as 60%–70% in patients with epilepsy, 391,392 but may be lower for refractory SE of other etiologies 393 . Perampanel, a noncompetitive AMPAR blocker, similarly has had anecdotal success with treatment of SE 394–396 and with the reduction of some seizure types in animal models of extreme SE 397 . However, conducting these clinicals trials is a difficult feat, and a recent clinical trial for treatment of refractory SE that compared ketamine infusion to traditional general anesthetic agents that target GABA‐ARs (KETASER01) was recently withdrawn because of eligibility requirments and unsuccessful recruitment 398 .…”