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Title: Persistent neuroinflammation and cognitive impairment in a rat model of acute diisopropylfluorophosphate intoxication.

Authors: Flannery, Brenna M; Bruun, Donald A; Rowland, Douglas J; Banks, Christopher N; Austin, Adam T; Kukis, David L; Li, Yonggang; Ford, Byron D; Tancredi, Daniel J; Silverman, Jill L; Cherry, Simon R; Lein, Pamela J

Published In J Neuroinflammation, (2016 Oct 12)

Abstract: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can trigger convulsions that progress to life-threatening status epilepticus. Survivors face long-term morbidity including mild-to-severe decline in memory. It is posited that neuroinflammation plays a key role in the pathogenesis of OP-induced neuropsychiatric deficits. Rigorous testing of this hypothesis requires preclinical models that recapitulate relevant phenotypic outcomes. Here, we describe a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) that exhibits persistent neuroinflammation and cognitive impairment.Neuroinflammation, neurodegeneration, and cognitive function were compared in adult male Sprague Dawley rats injected with an acutely toxic dose of DFP vs. vehicle controls at multiple time points up to 36 days post-exposure. Neuroinflammation was quantified using immunohistochemical biomarkers of microglia (ionized calcium-binding adapter molecule 1, IBA1) and activated astrocytes (glial fibrillary acidic protein, GFAP) and positron emission tomography (PET) imaging of [11C]-(R)-PK11195, a ligand for the 18-kDa mitochondrial membrane translocator protein (TSPO). FluoroJade-B staining was used to assess neurodegeneration; Pavlovian conditioning, to assess cognitive function.Animals exhibited moderate-to-severe seizures within minutes of DFP injection that continued for up to 6 h post-injection. As indicated by IBA1 and GFAP immunoreactivity and by PET imaging of TSPO, acute DFP intoxication triggered neuroinflammation in the hippocampus and cortex during the first 3 days that peaked at 7 days and persisted to 21 days post-exposure in most animals. Neurodegeneration was detected in multiple brain regions from 1 to 14 days post-exposure. All DFP-intoxicated animals exhibited significant deficits in contextual fear conditioning at 9 and 20 days post-exposure compared to vehicle controls. Whole-brain TSPO labeling positively correlated with seizure severity score, but did not correlate with performance in the contextual fear-conditioning task.We describe a preclinical model in which acute DFP intoxication causes seizures, persistent neuroinflammation, neurodegeneration, and memory impairment. The extent of the neuroinflammatory response is influenced by seizure severity. However, the observation that a subset of animals with moderate seizures and minimal TSPO labeling exhibited cognitive deficits comparable to those of animals with severe seizures and significant TSPO labeling suggests that DFP may impair learning and memory circuitry via mechanisms independent of seizures or neuroinflammation.

PubMed ID: 27733171 Exiting the NIEHS site

MeSH Terms: Animals; Calcium-Binding Proteins/metabolism; Carrier Proteins/metabolism; Cholinesterase Inhibitors/toxicity*; Cognitive Dysfunction/chemically induced*; Cognitive Dysfunction/diagnostic imaging; Conditioning, Classical/drug effects; Encephalitis/chemically induced*; Encephalitis/diagnostic imaging; Exploratory Behavior/drug effects; Glial Fibrillary Acidic Protein/metabolism; Isoflurophate/toxicity*; Magnetic Resonance Imaging; Male; Microfilament Proteins/metabolism; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Receptors, GABA-A/metabolism; Regression Analysis; Time Factors

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