Lipidomes of brain from rats acutely intoxicated with diisopropylfluorophosphate identifies potential therapeutic targets

Jun Yang, Donald A. Bruun, Chang Wang, Debin Wan, Cindy B. McReynolds, Kenny Phu, Bora Inceoglu, Pamela J. Lein, Bruce D. Hammock

Research output: Contribution to journalArticle

Abstract

Organophosphates (OPs), a class of phosphorus-containing chemicals that act by disrupting cholinergic transmission, include both toxic and fast-acting chemical warfare agents as well as less toxic but more easily accessible OP pesticides. The classical atropine/2-PAM antidote fails to protect against long-term symptoms following acute intoxication with OPs at levels that trigger status epilepticus. Acute OP intoxication also causes a robust neuroinflammatory response, which is implicated in the pathogenesis of long-term effects. In this study, we characterized the profiles of lipid mediators, important players in neuroinflammation, in the rat model of acute DFP intoxication. The profiles of lipid mediators were monitored in three different regions of the brain (cortex, hippocampus, and cerebellum) at 0, 1, 3, 7, 14, and 28 days post-exposure. The distribution pattern of lipid mediators was distinct in the three brain regions. In the cerebellum, the profile is dominated by LOX metabolites, while the lipid mediator profiles in cortex and hippocampus are dominated by COX metabolites followed by LOX and CYP 450 metabolites. Following acute DFP intoxication, most of the pro-inflammatory lipid mediators (e.g., PGD2 and PGE2) increased rapidly from day 1, while the concentrations of some anti-inflammatory lipid mediators (e.g. 14,15 EpETrE) decreased after DFP intoxication but recovered by day 14 post-exposure. The lipidomics results suggest two potential treatment targets: blocking the formation of prostaglandins by inhibiting COX and stabilizing the anti-inflammatory lipid mediators containing epoxides by inhibiting the enzyme soluble epoxide hydrolase (sEH).

Original languageEnglish (US)
Article number114749
JournalToxicology and Applied Pharmacology
Volume382
DOIs
StatePublished - Nov 1 2019

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Isoflurophate
Rats
Brain
Organophosphates
Lipids
Metabolites
Poisons
Cerebellum
Therapeutics
Hippocampus
Anti-Inflammatory Agents
Chemical Warfare Agents
Epoxide Hydrolases
Prostaglandin D2
Antidotes
Status Epilepticus
Epoxy Compounds
Atropine
Dinoprostone
Pesticides

Keywords

  • COX
  • DFP
  • Lipidomics
  • Regulatory lipid mediators
  • sEH

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Lipidomes of brain from rats acutely intoxicated with diisopropylfluorophosphate identifies potential therapeutic targets. / Yang, Jun; Bruun, Donald A.; Wang, Chang; Wan, Debin; McReynolds, Cindy B.; Phu, Kenny; Inceoglu, Bora; Lein, Pamela J.; Hammock, Bruce D.

In: Toxicology and Applied Pharmacology, Vol. 382, 114749, 01.11.2019.

Research output: Contribution to journalArticle

Yang, Jun ; Bruun, Donald A. ; Wang, Chang ; Wan, Debin ; McReynolds, Cindy B. ; Phu, Kenny ; Inceoglu, Bora ; Lein, Pamela J. ; Hammock, Bruce D. / Lipidomes of brain from rats acutely intoxicated with diisopropylfluorophosphate identifies potential therapeutic targets. In: Toxicology and Applied Pharmacology. 2019 ; Vol. 382.
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