Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

• Published in: Neurotoxicology (Park Forest South) 2021-12, Vol.87, p.106-119
• Main Authors: Calsbeek, Jonas J., González, Eduardo A., Bruun, Donald A., Guignet, Michelle A., Copping, Nycole, Dawson, Mallory E., Yu, Alexandria J., MacMahon, Jeremy A., Saito, Naomi H., Harvey, Danielle J., Silverman, Jill L., Lein, Pamela J.
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Acute intoxication; Animal models; Animals; Atropine; Benzodiazepines; Brain; Brain - drug effects; Brain - enzymology; Brain - pathology; Brain damage; Brain injury; Cholinesterase Inhibitors - pharmacology; Cognitive ability; Disease Models, Animal; Electroencephalography; Epilepsy; Exposure; Female; Inflammation; Intoxication; Isoflurophate - toxicity; Male; Mice; Mice, Inbred C57BL; Nerve agents; Nesting Behavior - drug effects; Neurodegeneration; Neuroinflammation; Neuroinflammatory Diseases - chemically induced; Neuroinflammatory Diseases - pathology; Neuroinflammatory Diseases - psychology; Neurotoxicity; Open Field Test; Organophosphate; Organophosphates; Pesticides; Seizures; Status Epilepticus - chemically induced; Status Epilepticus - pathology; Status Epilepticus - psychology
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2021.09.001

[Display omitted] •Acute DFP intoxication caused status epilepticus in the adult male C57BL/6J mouse.•DFP inhibited AChE in multiple brain regions for up to 14 d post-exposure.•DFP caused neurodegeneration and neuroinflammation for up to 28 d post-exposure.•Deficits in locomotor and home-cage behavior were observed at 28 d post-DFP.•Mice acutely intoxicated with DFP recapitulate effects observed in humans and rats. Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.