Editor's Highlight: Spatiotemporal Progression and Remission of Lesions in the Rat Brain Following Acute Intoxication With Diisopropylfluorophosphate.
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.
Translational Biology in the Department of Research, BioMarin Pharmaceuticals Inc, Novato, California, USA.
Sílvia
S
Sisó
Department of Molecular Biosciences School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Brad A
BA
Hobson
Department of Public Health Sciences School of Medicine, University of California-Davis, Davis, California, USA.
Danielle J
DJ
Harvey
Department of Molecular Biosciences School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Donald A
DA
Bruun
Department of Biomedical Engineering and the Center for Molecular and Genomic Imaging College of Engineering, University of California-Davis, Davis, California, USA.
Douglas J
DJ
Rowland
Biomedical Magnetic Resonance Laboratory, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
Joel R
JR
Garbow
Department of Molecular Biosciences School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Pamela J
PJ
Lein
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D007531:Isoflurophate / Q000633:toxicity*; D008297:Male; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology*; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D062211:Spatio-Temporal Analysis; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D007531:Isoflurophate
histopathology; neurodegeneration; neuroinflammation; organophosphate neurotoxicity