title: A rodent model of human organophosphate exposure producing status epilepticus and neuropathology.
abstract: Exposure to organophosphates (OPs) often results in seizures and/or status epilepticus (SE) that produce neural damage within the central nervous system (CNS). Early control of SE is imperative for minimizing seizure-related CNS neuropathology. Although standard therapies exist, more effective agents are needed to reduce OP-induced SE and neuronal loss, particularly therapies with efficacy when administered 10's of minutes after the onset of SE. To evaluate novel antiseizure compounds, animal models should simulate the CNS effects of OP exposure observed in humans. We characterized in rats the effects of the OP, diisopropyl flourophosphate (DFP) as a function of dose and route of administration of supporting agents (pyridostigmine, 2-PAM, atropine); outcome measures were mortality, electrographic seizure activity during SE, and subsequent CNS neuropathology. Doses of DFP between 3 and 7mg/kg consistently caused SE, and the latency to behavioral tremors and to subsequent initiation of SE were dose related. In distinction, all doses of DFP that resulted in electrographic SE (3-7mg/kg) produced seizures of similar intensity and duration, and similar CNS neuropathology (i.e., the effects were all-or-none). Although SE was similar across doses, mortality progressively increased with higher doses of DFP. Mortality was significantly lower when the route of administration of therapeutic agents was intramuscular compared to intraperitoneal. This rodent model of OP poisoning demonstrates pathological characteristics similar to those observed in humans, and thus begins to validate this model for investigating potential new therapeutic approaches.
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108-9999, United States.
authors.forename: W
authors.initials: W
authors.lastname: Pouliot
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108-9999, United States; Department of Pharmacology and Toxicology, University of Utah School of Medicine and College of Pharmacy, United States. Electronic address: steven.bealer@utah.edu.
authors.forename: S L
authors.initials: SL
authors.lastname: Bealer
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108-9999, United States.
authors.forename: B
authors.initials: B
authors.lastname: Roach
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108-9999, United States.
authors.forename: F E
authors.initials: FE
authors.lastname: Dudek
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000401:mortality; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D008297:Male; D010755:Organophosphates / Q000633:toxicity*; D044345:Phosphoric Triester Hydrolases / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy / Q000401:mortality
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D011220:Pralidoxime Compounds; D001285:Atropine; D044345:Phosphoric Triester Hydrolases; C020061:diisopropyl-fluorophosphatase; D011729:Pyridostigmine Bromide; C028797:pralidoxime
keywords: Antiseizure; EEG; Neuroprotection; Seizures; Status epilepticus