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Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABA_A) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.

A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABA_A receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.

Midazolam–ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate–midazolam or valproate–ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam–ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.

This study showed that a treatment aimed at correcting maladaptive GABA_A receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam–ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.