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Toxicol Sci. 2017 Jun 1;157(2):342-353. doi: 10.1093/toxsci/kfx049.

From the Cover: MagneticResonance Imaging Reveals Progressive Brain Injury in Rats Acutely Intoxicated With Diisopropylfluorophosphate.

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Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Translational Biology in the Department of Research, BioMarin Pharmaceuticals Inc, Novato, California, USA.
Department of Biomedical Engineering and the Center for Molecular and Genomic Imaging College of Engineering, University of California-Davis, Davis, CA, USA.
Department of Public Health Sciences School of Medicine, University of California-Davis, Davis, California, USA.
Biomedical Magnetic Resonance Laboratory, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.


Acute intoxication with organophosphates (OPs) can trigger seizures that progress to status epilepticus, and survivors often exhibit chronic neuropathology, cognitive impairment, affective disorders, and/or electroencephalographic abnormalities. Understanding how acute injury transitions to persistent neurological sequelae is critical to developing medical countermeasures for mitigating damage following OP-induced seizures. Here, we used in vivo magnetic resonance imaging (MRI) to monitor the spatiotemporal patterns of neuropathology for 1 month after acute intoxication with diisopropylfluorophosphate (DFP). 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. T2-weighted and diffusion-weighted MR imaging prior to DFP exposure and at 3, 7, 14, 21, or 28 days postexposure revealed prominent lesions, tissue atrophy, and ventricular enlargement in discrete brain regions. Lesions varied in intensity and/or extent over time, with the overall magnitude of injury strongly influenced by seizure severity. Importantly, lesions detected by MRI correlated spatially and temporally with histological evidence of brain pathology. Analysis of histogram parameters extracted from frequency distributions of regional apparent diffusion coefficient (ADC) values identified the standard deviation and 90th percentile of the ADC as robust metrics for quantifying persistent and progressive neuropathological changes. The interanimal and interregional variations observed in lesion severity and progression, coupled with potential reinjury following spontaneous recurrent seizures, underscore the advantages of using in vivo imaging to longitudinally monitor neuropathology and, ultimately, therapeutic response, following acute OP intoxication.


T2-weighted MRI; diffusion-weighted MRI; in vivo imaging; organophosphate

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