Skip to main content
eScholarship
Open Access Publications from the University of California

UC Davis

UC Davis Previously Published Works bannerUC Davis

Acute administration of diazepam or midazolam minimally alters long-term neuropathological effects in the rat brain following acute intoxication with diisopropylfluorophosphate.

  • Author(s): Supasai, Suangsuda
  • González, Eduardo A
  • Rowland, Douglas J
  • Hobson, Brad
  • Bruun, Donald A
  • Guignet, Michelle A
  • Soares, Sergio
  • Singh, Vikrant
  • Wulff, Heike
  • Saito, Naomi
  • Harvey, Danielle J
  • Lein, Pamela J
  • et al.

Published Web Location

https://doi.org/10.1016/j.ejphar.2020.173538
No data is associated with this publication.
Abstract

Acute intoxication with organophosphorus cholinesterase inhibitors (OPs) can trigger seizures that rapidly progress to life-threatening status epilepticus. Diazepam, long considered the standard of care for treating OP-induced seizures, is being replaced by midazolam. Whether midazolam is more effective than diazepam in mitigating the persistent effects of acute OP intoxication has not been rigorously evaluated. We compared the efficacy of diazepam vs. midazolam in preventing persistent neuropathology in adult male Sprague-Dawley rats acutely intoxicated with the OP diisopropylfluorophosphate (DFP). Subjects were administered pyridostigmine bromide (0.1 mg/kg, i.p.) 30 min prior to injection with DFP (4 mg/kg, s.c.) or vehicle (saline) followed 1 min later by atropine sulfate (2 mg/kg, i.m.) and pralidoxime (25 mg/kg, i.m.), and 40 min later by diazepam (5 mg/kg, i.p.), midazolam (0.73 mg/kg, i.m.), or vehicle. At 3 and 6 months post-exposure, neurodegeneration, reactive astrogliosis, microglial activation, and oxidative stress were assessed in multiple brain regions using quantitative immunohistochemistry. Brain mineralization was evaluated by in vivo micro-computed tomography (micro-CT). Acute DFP intoxication caused persistent neurodegeneration, neuroinflammation, and brain mineralization. Midazolam transiently mitigated neurodegeneration, and both benzodiazepines partially protected against reactive astrogliosis in a brain region-specific manner. Neither benzodiazepine attenuated microglial activation or brain mineralization. These findings indicate that neither benzodiazepine effectively protects against persistent neuropathological changes, and suggest that midazolam is not significantly better than diazepam. Overall, this study highlights the need for improved neuroprotective strategies for treating humans in the event of a chemical emergency involving OPs.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content

This item is under embargo until September 16, 2021.