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

Suangsuda Supasai; Eduardo A González; Douglas J Rowland; Brad Hobson; Donald A Bruun; Michelle A Guignet; Sergio Soares; Vikrant Singh; Heike Wulff; Naomi Saito; Danielle J Harvey; Pamela J Lein

doi:10.1016/j.ejphar.2020.173538

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

Eur J Pharmacol. 2020 Nov 5:886:173538. doi: 10.1016/j.ejphar.2020.173538. Epub 2020 Sep 6.

Authors

Affiliations

¹ Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA; Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand. Electronic address: ssupasai@ucdavis.edu.
² Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA. Electronic address: azgonzalez@ucdavis.edu.
³ Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA, 95616, USA. Electronic address: djrowland@ucdavis.edu.
⁴ Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA; Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA, 95616, USA. Electronic address: bahobson@ucdavis.edu.
⁵ Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA. Electronic address: dabruun@ucdavis.edu.
⁶ Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA. Electronic address: mguignet@ucdavis.edu.
⁷ Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA, 95616, USA. Electronic address: srpsoares@ucdavis.edu.
⁸ Department of Pharmacology, University of California, Davis, School of Medicine, Davis, CA, 95616, USA. Electronic address: vssingh@ucdavis.edu.
⁹ Department of Pharmacology, University of California, Davis, School of Medicine, Davis, CA, 95616, USA. Electronic address: hwulff@ucdavis.edu.
¹⁰ Department of Public Health Sciences, University of California, Davis, School of Medicine, Davis, CA, 95616, USA. Electronic address: nhsaito@ucdavis.edu.
¹¹ Department of Public Health Sciences, University of California, Davis, School of Medicine, Davis, CA, 95616, USA. Electronic address: djharvey@ucdavis.edu.
¹² Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA. Electronic address: pjlein@ucdavis.edu.

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.

Keywords: Benzodiazepines; Diazepam; Micro-CT; Midazolam; Neuroinflammation; Organophosphate neurotoxicity.

MeSH terms

Animals
Brain Diseases / chemically induced*
Brain Diseases / drug therapy*
Brain Diseases / pathology
Cholinesterase Inhibitors / poisoning*
Diazepam / therapeutic use*
GABA Modulators / therapeutic use*
Gliosis / chemically induced
Gliosis / drug therapy
Gliosis / pathology
Isoflurophate / poisoning*
Male
Microglia / drug effects
Midazolam / therapeutic use*
Neurodegenerative Diseases / chemically induced
Neurodegenerative Diseases / drug therapy
Neurodegenerative Diseases / pathology
Neurotoxicity Syndromes / drug therapy
Oxidative Stress / drug effects
Rats
Rats, Sprague-Dawley
Seizures / chemically induced
Seizures / drug therapy
X-Ray Microtomography

Substances

Cholinesterase Inhibitors
GABA Modulators
Isoflurophate
Diazepam
Midazolam

Abstract

MeSH terms

Substances

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