Summary: Objective: 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.Methods: 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.Results: 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.Significance: 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.

Hypoxic necrosis of dentate gyrus neurons in primary culture required the activation of an orderly cell death program independent of protein synthesis. Early mitochondrial swelling and loss of the mitochondrial membrane potential were accompanied by release of cytochrome c and followed by caspase-9-dependent activation of caspase-3. Caspase-3 and -9 inhibitors reduced neuronal necrosis. Calcium directly induced cytochrome c release from isolated mitochondria. Hypoxic neuronal necrosis may be an active process in which the direct effect of hypoxia on mitochondria may lead to the final common pathway of caspase-3-mediated neuronal death.

Summary: Status epilepticus in the immature brain induces neuronal injury in the hippocampal formation, but the mode and mechanism of death are poorly understood. Our laboratory has recently investigated the role of caspase‐3, ‐8, and ‐9 in neuronal injury, using a lithium–pilocarpine model of status epilepticus in 2‐week‐old rat pups. Our results showed that dying neurons in the dentate gyrus and CA1‐subiculum area do not share the same mechanism of death. In CA1‐subiculum, caspase‐8 upregulation preceded caspase‐3 activation in morphologically necrotic neurons. The pan‐caspase inhibitor Q‐VD‐OPH reduced CA1 damage, showing that caspases contribute to status epilepticus–induced necrosis. In the dentate gyrus, dying neurons were caspase‐9 and ‐3 immunoreactive and morphologically apoptotic. It is not clear why the same seizures cause different types of cell death in neurons that are connected in series along the same hippocampal circuit, but the apoptotic dentate neurons express doublecortin, and do not express calbindin‐D28k, suggesting that their immaturity may be a factor in producing an apoptotic mode of death.