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

Autor: Jonas J. Calsbeek, Naomi H. Saito, Jill L. Silverman, Danielle J Harvey, Michelle Guignet, Jeremy A. MacMahon, Nycole A. Copping, Donald A. Bruun, Mallory E. Dawson, Pamela J. Lein, Eduardo A. González, Alexandria J. Yu
Rok vydání: 2021
Předmět:
Male
Isoflurophate
Neurodegenerative
Pharmacology
Inbred C57BL
Toxicology
Nesting Behavior
Mice
chemistry.chemical_compound
Status Epilepticus
Neuroinflammation
Organophosphate
Nerve agent
General Neuroscience
Brain
Electroencephalography
Pharmacology and Pharmaceutical Sciences
Acetylcholinesterase
Atropine
Neurological
Female
medicine.symptom
medicine.drug
medicine.drug_class
Status epilepticus
Brain damage
Basic Behavioral and Social Science
Article
Vaccine Related
Seizures
Biodefense
Behavioral and Social Science
medicine
Animals
Neurodegeneration
Benzodiazepine
Animal
business.industry
Prevention
Neurosciences
Neurotoxicity
medicine.disease
Brain Disorders
Mice
Inbred C57BL
Disease Models
Animal
chemistry
Disease Models
Neuroinflammatory Diseases
Cholinesterase Inhibitors
business
Open Field Test
Zdroj: Neurotoxicology
ISSN: 0161-813X
Popis: 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.
Databáze: OpenAIRE
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