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      Editor’s Highlight: Spatiotemporal Progression and Remission of Lesions in the Rat Brain Following Acute Intoxication With Diisopropylfluorophosphate

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          Abstract

          Similar to organophosphate (OP) nerve agents, diisopropylfluorophosphate (DFP) rapidly and irreversibly inhibits acetylcholinesterase, leading to convulsions that can progress to status epilepticus (SE). However, in contrast to the OP nerve agents, the long-term consequences of DFP-induced SE are not well known. Thus, we characterized the spatiotemporal profile of neuropathology during the first 2 months following acute DFP intoxication. Adult, male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to successive administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im), and 2-pralidoxime (25 mg/kg, im), exhibited moderate-to-severe seizure behavior, yet survived until euthanized at 0.5 to 60 days post exposure. Analyses of brains and hearts stained with hematoxylin-eosin, or of brains immunostained for neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), or ionized binding adapter molecule 1 (IBA1), revealed progressive neuronal cell death, neuroinflammation, and tissue remodeling across limbic brain regions and the cerebral cortex, with no detectable pathology in the cerebellum or the heart. The lesion type and progression varied according to brain region and time after exposure. Across multiple brain regions, neuronal necrosis peaked after the first week, and neuroinflammation persisted at least 2 months after intoxication. Notably, mineralization was observed at later times in the thalamus, and to a more limited extent, in the hippocampus. Lesion severity was influenced by the initial seizure severity, and spontaneous recurrent seizures were associated with more severe brain damage. These findings parallel descriptions of neuropathology in preclinical models of acute intoxication with OP nerve agents, and other seizurogenic chemicals, suggesting conserved mechanisms of pathology downstream of chemical-induced SE.

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          Author and article information

          Journal
          Toxicol Sci
          Toxicol. Sci
          toxsci
          Toxicological Sciences
          Oxford University Press
          1096-6080
          1096-0929
          June 2017
          07 March 2017
          01 June 2018
          : 157
          : 2
          : 330-341
          Affiliations
          [* ]Translational Biology in the Department of Research, BioMarin Pharmaceuticals Inc, Novato, California 94949
          []Department of Molecular Biosciences School of Veterinary Medicine
          []Department of Public Health Sciences School of Medicine
          [§ ]Department of Biomedical Engineering and the Center for Molecular and Genomic Imaging College of Engineering, University of California-Davis, Davis, California 95616;
          []Biomedical Magnetic Resonance Laboratory, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri 63110
          Author notes
          [1]

          These authors contributed equally to this study.

          [2 ]To whom correspondence should be addressed at Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, 1089 Veterinary Medicine Drive, Davis, California 95618. Fax: (530) 752-7690. E-mail: pjlein@ 123456ucdavis.edu
          Article
          PMC6070115 PMC6070115 6070115 kfx048
          10.1093/toxsci/kfx048
          6070115
          28329845
          34220ec3-1d6e-488d-8739-3765065e9b77
          © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
          History
          Page count
          Pages: 12
          Funding
          Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
          Award ID: U54 NS079202
          Funded by: National Institute of General Medical Sciences 10.13039/100000057
          Award ID: T32 GM099608
          Funded by: David and Dana Loury Foundation
          Funded by: predoctoral fellowship
          Categories
          Brain Lesions following Diisopropylfluorophosphate

          histopathology,neuroinflammation,neurodegeneration,organophosphate neurotoxicity

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