Dexmedetomidine stops benzodiazepine-refractory nerve agent-induced status epilepticus

Abstract

Nerve agents are highly toxic chemicals that pose an imminent threat to soldiers and civilians alike. Nerve agent exposure leads to an increase in acetylcholine within the central nervous system, resulting in development of protracted seizures known as status epilepticus (SE). Currently, benzodiazepines are the standard of care for nerve agent-induced SE, but their efficacy quickly wanes as the time to treatment increases. Here, we examine the role of the α2-adrenoceptor in termination of nerve agent-induced SE using the highly specific agonist dexmedetomidine (DEX). Adult male rats were exposed to soman and entered SE as confirmed by electroencephalograph (EEG). We observed that administration of DEX in combination with the benzodiazepine midazolam (MDZ) 20 or 40 min after the onset of SE stopped seizures and returned processed EEG measurements to baseline levels. The protective effect of DEX was blocked by the α2-adrenoceptor antagonist atipamezole (ATI), but ATI failed to restore seizure activity after it was already halted by DEX in most cases, suggesting that α2-adrenoceptors may be involved in initiating SE cessation rather than merely suppressing seizure activity. Histologically, treatment with DEX + MDZ significantly reduced the number of dying neurons as measured by FluoroJade B in the amygdala, thalamus, and piriform cortex, but did not protect the hippocampus or parietal cortex even when SE was successfully halted. We conclude that DEX serves not just as a valuable potential addition to the anticonvulsant regimen for nerve agent exposure, but also as a tool for dissecting the neural circuitry that drives SE.

Validating a model of benzodiazepine refractory nerve agent-induced status epilepticus by evaluating the anticonvulsant and neuroprotective effects of scopolamine, memantine, and phenobarbital

“…Increasing doses of scopolamine did not lead to more rapid seizure control in this model, but latency to seizure termination was reduced by half compared to a similar model that did not utilize MDZ (Acon-Chen, et al, 2016). This supports the idea that polypharmacy and/or multimodal therapies offer the best hope for reliable termination of benzodiazepine-resistant SE (Koplovitz, et al, 2001;McCarren, et al, 2018;Niquet, et al, 2017;Wasterlain, et al, 2011;Weissman & Raveh, 2011).…”

“…Soman exposure was performed as previously described (Althaus, et al, 2017;McCarren, et al, 2018) and as detailed in Figure 1. HI-6 and atropine methyl nitrate (AMN) were employed to combat the peripheral effects of the OPNA and increase survival.…”

“…Images were captured using an Olympus BX50 microscope, DP71 camera, and cellSens Standard software (Olympus Corporation, Tokyo, Japan). Composite images of each region of interest were stitched together using FIJI and cropped as previously described (McCarren, et al, 2018). A treatment-blinded technician counted the number of FJB-expressing cells in each cropped region.…”

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

“…electrographic seizure activity and neuronal death. These effects are consistent with previously published results in the soman model of SE (McCarren et al, 2018). Additionally, DMT has been suggested to be an effective stand-alone treatment for SE in the amygdala kindling and the tetramethylenedisulfotetramine models, and has shown anticonvulsant activity as a pre-treatment in the kainic-acid model of SE (Halonen et al, 1995).…”

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

“…The rapid onset of toxicity and array of symptoms from OP exposures presents numerous challenges for first responders who must identify the exposure type and administer standard of care therapeutics (Deshpande et al, 2016; McCarren et al, 2018; Niquet et al, 2017a; Niquet et al, 2017b; Skovira et al, 2010). Thus, exposure to OPs presents a multi-tiered challenge to address a complex toxidrome that is dose- and time-sensitive.…”