Spatiotemporal progression and remission of lesions in the rat brain following acute intoxication with diisopropylfluorophosphate

Similar to organophosphate (OP) nerve agents, diisopropylfluorophosphate (DFP) rapidly and irreversibly inhibits acetylcholinesterase, leading to convulsions that can progress to status epilepticus (SE). However, in contrast to the OP nerve agents, the long-termconsequences of DFP-induced SE are not well known. Thus, we characterized the spatiotemporal profile of neuropathology during the first 2months following acute DFP intoxication. Adult,male Sprague Dawley rats administered pyridostigmine bromide (0.1mg/kg, im) 30min prior to successive administration of DFP (4mg/kg, sc), atropine sulfate (2mg/kg, im), and 2-pralidoxime (25mg/kg, im), exhibited moderate-to-severe seizure behavior, yet survived until euthanized at 0.5 to 60 days post exposure. Analyses of brains and hearts stained with hematoxylin-eosin, or of brains immunostained for neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), or ionized binding adaptermolecule 1 (IBA1), revealed progressive neuronal cell death, neuroinflammation, and tissue remodeling across limbic brain regions and the cerebral cortex, with no detectable pathology in the cerebellumor the heart. The lesion type and progression varied according to brain region and time after exposure. Acrossmultiple brain regions, neuronal necrosis peaked after the first week, and neuroinflammation persisted at least 2 months after intoxication. Notably,mineralization was observed at later times in the thalamus, and to amore limited extent, in the hippocampus. Lesion severity was influenced by the initial seizure severity, and spontaneous recurrent seizures were associated withmore severe brain damage. These findings parallel descriptions of neuropathology in preclinicalmodels of acute intoxication with OP nerve agents, and other seizurogenic chemicals, suggesting conservedmechanisms of pathology downstream of chemical-induced SE.