Neuroprotection by delayed triple therapy following sarin nerve agent insult in the rat

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

“…Sarin‐exposed rats with delayed midazolam treatment had significant loss of neurons, microglial activation, and gliosis, which was not observed in animals treated with midazolam–ketamine–valproate triple therapy. 96 We recently showed that the administration of midazolam–ketamine–phenobarbital triple therapy 40 minutes after seizure onset reduced seizure duration and provided nearly full neuroprotection in rats assessed at 2 weeks after soman exposure 19 (Figure 9 ). A silver stain to detect neurodegeneration showed that animals treated with triple therapy showed less neurodegeneration in fiber tracts, thalamus, amygdala, hippocampus, and piriform cortex compared with those receiving midazolam monotherapy.…”

“…and 45 mg/kg (i.v. ), respectively.” 100 Gore et al, 96 determined that the human equivalent of the triple therapy doses used in the Niquet 23 , 97 and Gore 96 studies is 0.48, 4.8, and 14.5 mg/kg for midazolam, ketamine, and valproate, respectively, which is similar to doses used in humans and thus, may be clinically applicable.…”

“…A recent study confirmed the efficacy of triple therapy for sarin‐induced SE. 96 The midazolam (3 mg/kg)–ketamine (30 mg/kg)–valproate (90 mg/kg) triple therapy administered 30 minutes after sarin‐induced seizure reduced initial seizure duration and reduced EEG power integral compared with midazolam treatment. These findings are in agreement with our findings in soman‐exposed rats in that although delayed treatment with midazolam increases survival, treatment with triple therapy of midazolam, ketamine, and valproate reduces EEG power integral.…”

“…These findings are in agreement with our findings in soman‐exposed rats in that although delayed treatment with midazolam increases survival, treatment with triple therapy of midazolam, ketamine, and valproate reduces EEG power integral. 21 Importantly, Gore et al 96 demonstrated that even 1 hour after sarin‐induced seizure, triple therapy is effective at terminating seizure. This window of therapeutic opportunity to treat with simultaneous triple therapy ASMs is important since in the event of mass casualties following exposure to OPNA (eg sarin and soman), a delay in rapidly treating all exposed patients is highly probable.…”

“…In the open field, rodents tend to spend less time in the center of the maze; historically, drugs that reduce anxiety‐like behavior increase time in the center of the maze (reviewed in Prut and Belzung 119 ). Gore et al 96 observed that sarin exposed animals (untreated) had a 400% increase in time spent in the center of an open field arena (1 m x 1 m) compared with control rats unexposed to sarin when evaluated 3 weeks after exposure. 96 In the midazolam monotherapy group treated 30 but not 60 minutes after exposure, the time spent in center was reduced but still significantly higher than in controls.…”