Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication.

Animals Behavior, Animal Brain / metabolism Disease Models, Animal Inflammation / chemically induced Isoflurophate / toxicity Male Neurotoxicity Syndromes / metabolism Organophosphate Poisoning / metabolism Oxidative Stress / drug effects Rats Rats, Sprague-Dawley Status Epilepticus / chemically induced
Behavior Cognition Diisopropylfluorophosphate Electroencephalography Microgliosis Persistent effects Preclinical model Reactive astrogliosis Spontaneous recurrent seizures Sublethal toxicity

Journal

Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169

Informations de publication

Date de publication:
01 2020
Historique:
received: 22 12 2018
revised: 05 03 2019
accepted: 20 03 2019
pubmed: 25 3 2019
medline: 15 12 2020
entrez: 26 3 2019
Statut: ppublish

Résumé

Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.

Identifiants

DOI: 10.1016/j.nbd.2019.03.019 PMID: 30905768 PMC: PMC6754818
pubmed: 30905768
pii: S0969-9961(19)30073-7
doi: 10.1016/j.nbd.2019.03.019
pmc: PMC6754818
mid: NIHMS1525963
pii:
doi:

Substances chimiques

Isoflurophate 12UHW9R67N

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

104431

Subventions

Organisme : NIGMS NIH HHS
ID : T32 GM099608
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD079125
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS079202
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Michelle Guignet (M)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA. Electronic address: mguignet@ucdavis.edu.

Kiran Dhakal (K)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.

Brenna M Flannery (BM)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.

Brad A Hobson (BA)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA. Electronic address: bahobson@ucdavis.edu.

Dorota Zolkowska (D)

Department of Neurology, School of Medicine, University of California-Davis, 4860 Y Street, Sacramento, CA 95817, USA. Electronic address: dzolkowska@ucdavis.edu.

Ashish Dhir (A)

Department of Neurology, School of Medicine, University of California-Davis, 4860 Y Street, Sacramento, CA 95817, USA. Electronic address: dhir@ucdavis.edu.

Donald A Bruun (DA)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA. Electronic address: dabruun@ucdavis.edu.

Shuyang Li (S)

Department of Public Health Sciences, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: shyli@ucdavis.edu.

Abdul Wahab (A)

Department of Neurology, School of Medicine, University of California-Davis, 4860 Y Street, Sacramento, CA 95817, USA.

Danielle J Harvey (DJ)

Department of Public Health Sciences, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: djharvey@ucdavis.edu.

Jill L Silverman (JL)

Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California-Davis, 2230 Stockton Boulevard, Sacramento, CA 95817, USA; MIND Institute, School of Medicine, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA. Electronic address: jsilverman@ucdavis.edu.

Michael A Rogawski (MA)

Department of Neurology, School of Medicine, University of California-Davis, 4860 Y Street, Sacramento, CA 95817, USA. Electronic address: rogawski@ucdavis.edu.

Pamela J Lein (PJ)

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA; MIND Institute, School of Medicine, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA. Electronic address: pjlein@ucdavis.edu.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Persistent behavior deficits,...
Recherchemedicale.com › Comportement et mécanismes comportementaux › Comportement › Comportement animal › Persistent behavior deficits,...
Recherchemedicale.com › Système nerveux › Système nerveux central › Encéphale › Persistent behavior deficits,...
Recherchemedicale.com › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Persistent behavior deficits,...
Recherchemedicale.com › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Persistent behavior deficits,...
Recherchemedicale.com › Composés chimiques organiques › Composés organiques du phosphore › Phosphonates › Phosphonofluoridates › Isoflurophate › Persistent behavior deficits,...
Recherchemedicale.com › Troubles dus à des produits chimiques › Intoxication › Syndromes neurotoxiques › Persistent behavior deficits,...
Recherchemedicale.com › Troubles dus à des produits chimiques › Intoxication › Intoxication aux organophosphates › Persistent behavior deficits,...
Recherchemedicale.com › Phénomènes physiologiques › Stress physiologique › Stress oxydatif › Persistent behavior deficits,...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Persistent behavior deficits,...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Rat Sprague-Dawley › Persistent behavior deficits,...
Recherchemedicale.com › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Crises épileptiques › État de mal épileptique › Persistent behavior deficits,...