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

Details

• Alternative Title:
  J Pharmacol Toxicol Methods
• Personal Author:
  Jackson, Cecelia ; Ardinger, Cherish ; Winter, Kristin M. ; McDonough, John H. ; McCarren, Hilary S.
• Description:
  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 five brain regions. Each treatment provided significant protection compared to saline + midazolam in at least two brain regions.
  
  Discussion:
  
  Because our data agree with previously published studies on the efficacy of these compounds, we conclude that this model is a valid way to test novel anticonvulsants/ neuroprotectants for controlling benzodiazepine-resistant OPNA-induced SE and subsequent neuropathology.
  
  
• Subjects:
  Animals Anticonvulsants Article Atropine Benzodiazepines Brain Electroencephalography Male Memantine Methods Midazolam Nerve Agent Nerve Agents Neuroprotective Agents Phenobarbital Rats Rats, Sprague-Dawley Scopolamine Seizure Seizures Soman Status Epilepticus

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• Source:
  J Pharmacol Toxicol Methods. 97:1-12
• Pubmed ID:
  30790623
• Pubmed Central ID:
  PMC6529248
• Document Type:
  Journal Article
• Funding:
  AOD18013-001/CD/ODCDC CDC HHS/United States
• Volume:
  97
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:596909240e9fed8ee9a0ebbf26fcd64396a63d8e6535c3ef3693be710a2ba4c2
• Download URL:
  https://stacks.cdc.gov/view/cdc/106600/cdc_106600_DS1.pdf
• File Type:
  [PDF - 1.29 MB ]