Corticosterone primes the neuroinflammatory response to Gulf War Illness‐relevant organophosphates independently of acetylcholinesterase inhibition

Details

• Alternative Title:
  J Neurochem
• Personal Author:
  Locker, Alicia R. ; Michalovicz, Lindsay T. ; Kelly, Kimberly A. ; Miller, Julie V. ; Miller, Diane B. ; O'Callaghan, James P.
• Description:
  Gulf War Illness (GWI) is a chronic multi‐symptom disorder affecting veterans of the 1991 Gulf War. Among the symptoms of GWI are those associated with sickness behavior, observations suggestive of underlying neuroinflammation. We have shown that exposure of mice to the stress hormone, corticosterone (CORT), and to diisopropyl fluorophosphate (DFP), as a nerve agent mimic, results in marked neuroinflammation, findings consistent with a stress/neuroimmune basis of GWI. Here, we examined the contribution of irreversible and reversible acetylcholinesterase (AChE) inhibitors to neuroinflammation in our mouse model of GWI. Male C57BL/6J mice received 4 days of CORT (400 mg/L) in the drinking water followed by a single dose of chlorpyrifos oxon (CPO; 8 mg/kg, i.p.), DFP (4 mg/kg, i.p.), pyridostigmine bromide (PB; 3 mg/kg, i.p.), or physostigmine (PHY; 0.5 mg/kg, i.p.). CPO and DFP alone caused cortical and hippocampal neuroinflammation assessed by qPCR of tumor necrosis factor‐alpha, IL‐6, C–C chemokine ligand 2, IL‐1β, leukemia inhibitory factor and oncostatin M; CORT pretreatment markedly augmented these effects. Additionally, CORT exposure prior to DFP or CPO enhanced activation of the neuroinflammation signal transducer, signal transducer and activator of transcription 3 (STAT3). In contrast, PHY or PB alone or with CORT pretreatment did not produce neuroinflammation or STAT3 activation. While all of the CNS‐acting AChE inhibitors (DFP, CPO, and PHY) decreased brain AChE activity, CORT pretreatment abrogated these effects for the irreversible inhibitors. Taken together, these findings suggest that irreversible AChE inhibitor‐induced neuroinflammation and particularly its exacerbation by CORT, result from non‐cholinergic effects of these compounds, pointing potentially to organophosphorylation of other neuroimmune targets.
• Subjects:
  Acetylcholinesterase Animals Brain Cholinesterase Inhibitors Corticosterone Disease Models, Animal Gulf War Male Mice, Inbred C57BL Organophosphates Persian Gulf Syndrome Pyridostigmine Bromide

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• Source:
  J Neurochem. 142(3):444-455
• Pubmed ID:
  28500787
• Pubmed Central ID:
  PMC5575502
• Document Type:
  Journal Article
• Volume:
  142
• Issue:
  3
• NIOSHTIC Number:
  nn:20049836
• Collection(s):
  CDC Public Access National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:58cc641f3aa0918f6e3c26b3d95d35cb521d1bbd60edbaa8fd64597ab90e08b68355fd526fcbb14862f49d4b271eb39c37216a4ce6bca424d29ec23f228bde9e
• Download URL:
  https://stacks.cdc.gov/view/cdc/118757/cdc_118757_DS1.pdf
• File Type:
  [PDF - 844.05 KB ]