TY - JOUR
T1 - Magnetic resonance imaging reveals progressive brain injury in rats acutely intoxicated with diisopropylfluorophosphate
AU - Hobson, Brad A.
AU - Sisó, Sílvia
AU - Rowland, Douglas J.
AU - Harvey, Danielle J.
AU - Bruun, Donald A.
AU - Garbow, Joel R.
AU - Lein, Pamela J.
N1 - Funding Information:
The authors thank Jennifer Fung and Charles Smith (UC Davis Center for Molecular and Genomic Imaging) for their assistance with animal care and imaging, Dr Simon Cherry (UC Davis) for advice on experimental design, and both Dr Heike Wulff (UC Davis) and Dr Daniel Tancredi (UC Davis) for providing helpful feedback on early drafts of the manuscript. CounterACT Program, National Institutes of Health Office of the Director and the National Institute of Neurological Disorders and Stroke [U54 NS079202 to P.J.L.], the National Institute of General Medical Sciences [T32 GM099608 to B.A.H.], the David and Dana Loury Foundation (predoctoral fellowship to B.A.H.] and the ARCS Foundation (predoctoral fellowship to B.A.H.]. The sponsors were not involved in the study design, the collection, analysis and interpretation of data, in the writing of the paper or in the decision to submit the work for publication.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.
PY - 2017/6
Y1 - 2017/6
N2 - 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) 30min 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.
AB - 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) 30min 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.
KW - Diffusion-weighted MRI
KW - In vivo imaging
KW - Organophosphate
KW - T2-weighted MRI
UR - http://www.scopus.com/inward/record.url?scp=85021709053&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfx049
DO - 10.1093/toxsci/kfx049
M3 - Article
C2 - 28329842
AN - SCOPUS:85021709053
VL - 157
SP - 342
EP - 353
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -