The chemical convulsant diisopropylfluorophosphate (DFP) causes persistent neuropathology in adult male rats independent of seizure activity

Abstract

Organophosphate (OP) threat agents can trigger seizures that progress to status epilepticus, resulting in persistent neuropathology and cognitive deficits in humans and preclinical models. However, it remains unclear whether patients who do not show overt seizure behavior develop neurological consequences. Therefore, this study compared two subpopulations of rats with a low versus high seizure response to diisopropylfluorophosphate (DFP) to evaluate whether acute OP intoxication causes persistent neuropathology in non-seizing individuals. Adult male Sprague Dawley rats administered DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im), and pralidoxime (25 mg/kg, im) were monitored for seizure activity for 4 h post-exposure. Animals were separated into groups with low versus high seizure response based on behavioral criteria and electroencephalogram (EEG) recordings. Cholinesterase activity was evaluated by Ellman assay, and neuropathology was evaluated at 1, 2, 4, and 60 days post-exposure by Fluoro-Jade C (FJC) staining and micro-CT imaging. DFP significantly inhibited cholinesterase activity in the cortex, hippocampus, and amygdala to the same extent in low and high responders. FJC staining revealed significant neurodegeneration in DFP low responders albeit this response was delayed, less persistent, and decreased in magnitude compared to DFP high responders. Micro-CT scans at 60 days revealed extensive mineralization that was not significantly different between low versus high DFP responders. These findings highlight the importance of considering non-seizing patients for medical care in the event of acute OP intoxication. They also suggest that OP intoxication may induce neurological damage via seizure-independent mechanisms, which if identified, might provide insight into novel therapeutic targets.

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

“…However, a time‐course examination of temporal, morphological, and memory function changes is beyond the scope of this study, which is intended to capture the long‐term impact of NA exposure. There are a few previous studies on the temporospatial progression of neuroinflammation in a rat model of DFP intoxication 56–58 . These reports are consistent with our results on the persistent, long‐term neuropathological dysfunction in the soman model.…”

“…There are a few previous studies on the temporospatial progression of neuroinflammation in a rat model of DFP intoxication. [56][57][58] These reports are consistent with our results on the persistent, long-term neuropathological dysfunction in the soman model. However, potential differences in temporal aspects of neuroinflammation were also observed, such as its persistence for 3 months postexposure to soman.…”

“…In a micro-CT scan study in DFP-exposed rats, OP intoxication can produce neurological damage via seizure-independent mechanisms. 56 In somanintoxicated guinea pigs, there is a long-lasting Figure 11. Correlation between long-term decrease in the MRI-measured HV and behavioral spatial memory deficit in somanexposed rats.…”

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

“…Overall, the present results are consistent with previous studies of OP-induced SE, in which it was concluded that neurodegeneration and neuroinflammation are mediated by independent mechanisms, 92 and that seizure severity and duration are not the only variables driving neuronal cell loss. 90 In conclusion, our results confirm that MDZ at a dose equivalent to that recommended for the treatment of OP nerve agent seizures does not terminate DFP-induced SE in a rat model when administered 40 min after seizure onset. However, when ALLO or ALLO + PPL are administered with the same dose of MDZ, SE is generally terminated and there is reduced neurodegeneration.…”

“…Intermittent seizures and brief seizure relapse were observed in the 3-day period after treatment with the three-drug combination, likely due to the persistence of brain cholinesterase inhibition. 89,90 We do not consider the occurrence of such early spontaneous seizures to be an indication of epileptogenesis. However, the animals in the MDZ-only group exhibited spontaneous seizures that persisted for up to 7.5 months and clearly had become epileptic.…”