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

Abstract

Introduction: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time. To address this issue, we have developed a rat model to test novel anticonvulsant/ neuroprotectant adjuncts at delayed time points. Methods: For model development, adult male rats with cortical electroencephalographic (EEG) electrodes were exposed to soman and administered saline along with atropine, 2-PAM, and midazolam 5, 20, or 40 minutes after SE onset. We validated our model using three drugs: scopolamine, memantine, and phenobarbital. Using the same procedure outlined above, rats were given atropine, 2-PAM, midazolam and test treatment 20 minutes after SE onset. Results: Using gamma power, delta power, and spike rate to quantify EEG activity, we found that scopolamine was effective, memantine was minimally effective, and phenobarbital had a delayed effect on terminating SE. Fluoro-Jade B staining was used to assess neuroprotection in *

Phenobarbital as alternate anticonvulsant for organophosphate‐induced benzodiazepine‐refractory status epilepticus and neuronal injury

“…In conclusion, these results are consistent with recent reports in nerve agent models 31,32 and confirm that phenobarbital is an effective anticonvulsant for controlling DFP‐induced, benzodiazepine‐refractory SE when given at or after 40 minutes. It has significant protective effect against DFP‐induced massive neuronal injury and degeneration, indicating its neuroprotectant action.…”

“…Barbiturates that are positive allosteric modulators of GABA‐A receptors appear to be more effective and long‐lasting than benzodiazepines to control seizures, even when administered very late after OP exposure. Phenobarbital has been shown to mitigate the seizures and lethal effects caused by OP neurotoxicity 30,31 . However, the overall efficacy and safety of phenobarbital as a delayed (>40 minutes) postexposure anticonvulsant antidote for nerve agents are poorly understood.…”

“…Phenobarbital is used as second‐line drug for refractory SE, irrespective of the seizure etiology. Phenobarbital has been tested in a few animal models of OP intoxication 30‐32 . Based on overall survival rate, functional seizure suppression, and histological neurodegeneration outcomes, phenobarbital at 60 mg/kg may be a better option of the other two phenobarbital doses in DFP‐induced epilepsy, especially for ambulatory treatment.…”

“…Patients administered therapeutic or high dosages of phenobarbital for OP‐induced SE must often remain under clinical observation for airway and cardio‐respiratory vital functions, including continuous monitoring of blood pressure and respiratory rate. Because of the strong anticonvulsant property of phenobarbital, it could be used as an alternative to diazepam or midazolam to control SE after nerve agent exposure 4,30‐32 . However, the risk vs benefit of phenobarbital therapy, especially neurological morbidity of varying phenobarbital dosage, for OP‐induced SE remains unclear.…”

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

“…The intent of this treatment protocol was to avoid inducing levels of sedation that would require hospitalization. Therefore, we tested the clinical rat-equivalent PHB dose (Nair and Jacob, 2016 previously published results in the kainate model at 30 mg/kg PHB, as well as in the soman-induced SE model (i.e., nerve agent) at 100 mg/kg (Jackson et al, 2019). The effect of PHB as an adjunctive treatment to standard-of-care in our model validates the potential of this screening tool to identify treatments that will enhance the effects of MDZ on seizures and neuronal death; however, due to the sedative effects of barbiturates, this is not an optimal choice for adjunct, pre-hospital therapy.…”