Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Dhir, Ashish; Bruun, Donald A.; Guignet, Michelle; Tsai, Yi Hua; González, Eduardo; Calsbeek, Jonas J.; Vu, Joan; Saito, Naomi; Tancredi, Daniel J.; Harvey, Danielle; Lein, Pamela J.; Rogawski, Michael A.

doi:10.1111/nyas.14479

Cited by 22 publications

(14 citation statements)

References 90 publications

(207 reference statements)

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“…Animals were housed in a 12 h light-dark cycle with access to food and water provided ad libitum. Animals were acutely intoxicated with DFP (n = 10) as previously described [ 43 ]. Vehicle (VEH, n = 15) controls were administered saline instead of DFP but were otherwise similarly treated.…”

Section: Methodsmentioning

confidence: 99%

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease

Guignet¹,

Schmuck²,

Harvey³

et al. 2023

Heliyon

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Section: Methodsmentioning

confidence: 99%

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease

Guignet¹,

Schmuck²,

Harvey³

et al. 2023

Heliyon

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“…A multipronged combination approach to therapy may deliver more rapid and efficacious results, especially with refractory SE. NMDAR blockade together with a BZD quickly terminates SE, 130,358,366,367 allopregnanalone with perampanel works after BZD failure, 368 and triple therapy is superior to dual or monotherapy with phenobarbital, ketamine, and/or midazolam 124 . The synergistic supralinear benefits of rational polytherapy outweigh additive linear toxicities, 369 and simultaneous delivery is better than sequential 364,370 .…”

Section: Treatment Implications Of Differential Receptor Traffickingmentioning

confidence: 99%

In the fast lane: Receptor trafficking during status epilepticus

Naylor

2023

Epilepsia Open

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Status epilepticus (SE) remains a significant cause of morbidity and mortality and often is refractory to standard first‐line treatments. A rapid loss of synaptic inhibition and development of pharmacoresistance to benzodiazepines (BZDs) occurs early during SE, while NMDA and AMPA receptor antagonists remain effective treatments after BZDs have failed. Multimodal and subunit‐selective receptor trafficking within minutes to an hour of SE involves GABA‐A, NMDA, and AMPA receptors and contributes to shifts in the number and subunit composition of surface receptors with differential impacts on the physiology, pharmacology, and strength of GABAergic and glutamatergic currents at synaptic and extrasynaptic sites. During the first hour of SE, synaptic GABA‐A receptors containing γ2 subunits move to the cell interior while extrasynaptic GABA‐A receptors with δ subunits are preserved. Conversely, NMDA receptors containing N2B subunits are increased at synaptic and extrasynaptic sites, and homomeric GluA1 (“GluA2‐lacking”) calcium permeant AMPA receptor surface expression also is increased. Molecular mechanisms, largely driven by NMDA receptor or calcium permeant AMPA receptor activation early during circuit hyperactivity, regulate subunit‐specific interactions with proteins involved with synaptic scaffolding, adaptin‐AP2/clathrin‐dependent endocytosis, endoplasmic reticulum (ER) retention, and endosomal recycling. Reviewed here is how SE‐induced shifts in receptor subunit composition and surface representation increase the excitatory to inhibitory imbalance that sustains seizures and fuels excitotoxicity contributing to chronic sequela such as “spontaneous recurrent seizures” (SRS). A role for early multimodal therapy is suggested both for treatment of SE and for prevention of long‐term comorbidities.

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“…Perampanel also reduces the frequency of focal electrographic seizures in mice that exhibit spontaneous recurrent seizures following intrahippocampal injection of kainic acid (Twele et al 2015). Finally, perampanel suppresses behavioral and electrographic seizures in the rat lithium-pilocarpine (Hanada et al 2014) and diisopropylfluorophosphate (Dhir et al 2020) models of status epilepticus.…”

Section: Introductionmentioning

confidence: 96%

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

2021

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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.

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Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Cited by 22 publications

References 90 publications

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease

In the fast lane: Receptor trafficking during status epilepticus

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

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