A magnetic resonance imaging study of early brain injury in a rat model of acute DFP intoxication

Abstract

Current treatments for seizures induced by organophosphates do not protect sufficiently against progressive neurodegeneration or delayed cognitive impairment. Developing more effective therapeutic approaches has been challenging because the pathogenesis of these delayed consequences is poorly defined. Using magnetic resonance imaging (MRI), we previously reported brain lesions that persist for months in a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP). However, the early spatiotemporal progression of these lesions remains unknown. To address this data gap, we used in vivo MRI to longitudinally monitor brain lesions during the first 3 d following acute DFP intoxication. Adult male Sprague Dawley rats acutely intoxicated with DFP (4mg/kg, sc) were MR imaged at 6, 12, 18, 24, 48, 72h post-DFP, and their brains then taken for correlative histology to assess neurodegeneration using FluoroJade C (FJC) staining. Acute DFP intoxication elicited moderate-to-severe seizure activity. T2-weighted (T2w) anatomic imaging revealed prominent lesions within the thalamus, piriform cortex, cerebral cortex, hippocampus, corpus striatum, and substantia nigra that corresponded to neurodegeneration, evident as bands of FJC positive cells. Semi-quantitative assessment of lesion severity demonstrated significant regional variation in the onset and progression of injury, and suggested that lesion severity may be modulated by isoflurane anesthesia. These results imply that the timing of therapeutic intervention for attenuating brain injury following OP intoxication may be regionally dependent, and that longitudinal assessment of OP-induced damage by MRI may be a powerful tool for assessing therapeutic response.

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

“…Central nervous system manifestations after OP exposure include convulsive seizures and status epilepticus (SE), which can last 30 minutes or longer causing profound brain damage that results in neuronal damage or death (Chen, 2012;Hobson et al, 2018;Scholl et al, 2018). 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).…”

Magnetic resonance imaging analysis of long‐term neuropathology after exposure to the nerve agent soman: correlation with histopathology and neurological dysfunction

“…T2-weighted images and their associated T2 relaxation times, are frequently used to identify anatomical changes, such as tissue loss or the presence of lesions, in landmark regions, such as the hippocampus. 28,29 Diffusion tensor imaging has been used to generate apparent diffusion coefficient (ADC) maps to identify symptoms, such as restricted diffusion or edema. 30,31 CWNA exposure is known to cause rapid damage to the hippocampus, which is involved in major pathways associated with memory function and epilepsy, [32][33][34] even compared with other brain structures.…”

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

“…The International League Against Epilepsy defines SE as continuous seizure activity that lasts for 5 min or more and recognizes that if seizures persist for more than 30 min, there is a high risk of long-term consequences, 69 such as neurodegeneration, epileptogenesis, and cognitive decline. 7,64,[70][71][72][73] Here, we administered treatments at 40 min, a time in the evolution of SE where there is irreversible morbidity. SE in rats receiving 4 mg/kg DFP along with atropine and 2-PAM usually survive although some animals do succumb, which was the case for 25% of the animals in our vehicle treatment group.…”