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

Abstract

BackgroundAcute 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.MethodsNeuroinflammation, 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.ResultsAnimals 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.ConclusionsWe 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.

Neuroinflammation trajectories precede cognitive impairment after experimental meningitis—evidence from an in vivo PET study

“…We found increased expression of microglial markers IBA-1 and CD11B in the meningitis rat hippocampus 10 days after meningitis induction. The strong association between the overexpression of glial proteins and cognitive impairment has been reported in different disease models [52,53]. Because TSPO overexpression was also detected in reactive astrocytes [54], we determined GFAP protein expression, which was increased in both the 24-h and 10-day meningitis groups.…”

Neuroinflammation in Alzheimer’s disease: Pleiotropic roles for cytokines and neuronal pentraxins

“…Chronic neuroinflammation causes a sustained cytokine release, which can ultimately compromise brain tissue through inflammatory, atrophic effects on brain volume [47]. This process leads to neurodegeneration and cognitive deficits [48,49], which are known to be associated with AD [10,11,50]. …”

Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents

“…Sarin is one of the most widely used nerve agents, as evident from recent attacks in Syria and Japan (Yanagisawa et al, 2006;Dolgin, 2013;Rosman et al, 2014). OP pesticidesdiisopropylfluorophosphate (DFP), parathion, and paraoxonare considered credible threat agents (Bouzarth and Himwich, 1952;Baille-Le Crom et al, 1995;Kadriu et al, 2009;Wright et al, 2010;Liu et al, 2012;Ferchmin et al, 2014;Li et al, 2015;Flannery et al, 2016). DFP is a potential terrorist threat agent (see Sisó et al (2017)).…”

“…Brain damage is thought to occur not only by seizure-related excitotoxicity (Shih et al, 2003;Prager et al, 2013) but also via mechanisms independent of seizures such as activation of glia and cellular inflammation (Yokoyama, 2007;Banks and Lein, 2012;Pereira et al, 2014). The effects of OP intoxication are long lasting, and survivors suffer chronic brain damage including the risk of neurologic and cognitive deficits (Shih et al, 2003;Yokoyama, 2007;Liu et al, 2012;Prager et al, 2013;Li et al, 2015;Rojas et al, 2015;Flannery et al, 2016;Sisó et al, 2017).…”