Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors

NEUROPHARMACOLOGY

卷:185

Article

Lumley, Lucille¹  Niquet, Jerome²  Marrero-Rosado, Brenda¹  Schultz, Mark¹  Rossetti, Franco³  Furtado, Marcio de Araujo⁴  Wasterlain, Claude² 

[1] US Army Med Res Inst Chem Def, Neurosci Dept, Aberdeen Proving Ground, MD 21010 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Epilepsy Res Lab 151,Vet Affairs Greater Los Ange, Los Angeles, CA 90095 USA

[3] Walter Reed Army Inst Res, Mil Psychiat & Neurosci Dept, Silver Spring, MD USA

[4] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA

关键词: Ketamine;    Seizure;    Pharmacoresistance;    Organophosphorus;    Soman;    Pilocarpine;   

DOI  :  10.1016/j.neuropharm.2020.108444

来源: Elsevier

【 摘 要 】

The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABA(A)R) and increased N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABA(A)R and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABA(A)R modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Est1-/- mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABA(A)R may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergicinduced SE. Supplementing that treatment with valpmate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valpmate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

【 授权许可】

Free