Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Niquet, Jerome; Nguyen, Donna; de Araujo Furtado, Marcio; Lumley, Lucille

doi:10.1002/epi4.12713

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Journal Article · Fri Mar 10 00:00:00 EST 2023 · Epilepsia Open

DOI:https://doi.org/10.1002/epi4.12713· OSTI ID:1961005

^[1]; Nguyen, Donna ^[2]; de Araujo Furtado, Marcio ^[3]; ^[2]

Department of Neurology David Geffen School of Medicine at UCLA Los Angeles California USA, Epilepsy Research Laboratory Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California USA
Neuroscience Department U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) Aberdeen Proving Ground Maryland USA
BioSEaD, LLC Rockville Maryland USA

Abstract

Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA _A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 ^−/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institute of Neurological Disorders and Stroke; USDOE; USDOE Office of Science (SC); VA Office of Research and Development

Grant/Contract Number:: SC0014664

OSTI ID:: 1961005

Alternate ID(s):: OSTI ID: 2469763
OSTI ID: 1973299

Journal Information:: Epilepsia Open, Journal Name: Epilepsia Open Journal Issue: S1 Vol. 8; ISSN 2470-9239

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Country unknown/Code not available

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
ketamine
midazolam
neurosciences & neurology
pharmacoresistance
pilocarpine
seizure
soman

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

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