Corticosterone Primes the Neuroinflammatory Response to Gulf-War Illness-Relevant Organophosphates Independently of Acetylcholinesterase Inhibition

Details

• Journal Article:
  Journal of Neurochemistry
• 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 four days of CORT (400 mg/L) in the drinking water followed by a single dose of chlorpyrifos (CPO; 8 mg/kg, i.p.), DFP (4 mg/kg, i.p.), pyridostigmine (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 TNF-a, IL-6, C-C chemokine ligand 2 (CCL2), IL-1B, leukemia inhibitory factor (LIF) and oncostatin M (OSM); CORT pretreatment markedly augmented these effects. Additionally, CORT exposure prior to DFP or CPO enhanced activation of the neuroinflammation signal transducer, 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. [Description provided by NIOSH]
• Subjects:
  Acetylcholinesterase Animals Brain Cholinesterase Inhibitors Corticosterone Endocrine System Fatigue Gulf War Laboratories Mice, Inbred C57BL Nervous System Occupational Health Organophosphates Persian Gulf Syndrome Pyridostigmine Bromide Safety

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• Keywords:
  Author Keywords: Chlorpyrifos; Diisopropyl Fluorophosphate; STAT3; Neuroinflammation; Pyridostigmine Bromide; Physostigmine Military Personnel; Neurological Diseases; Laboratory Animals; Hormones; Acetylcholinesterase; Chlorpyrifos; Brain Function; Fatigue; Cognitive Function; Nerve Function;
• Source:
  J Neurochem 2017 Aug; 142(3):444-455
• ISSN:
  0022-3042
• Pubmed ID:
  28500787
• Pubmed Central ID:
  PMC5575502
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  12 pdf pages
• Volume:
  142
• Issue:
  3
• NIOSHTIC Number:
  nn:20049836
• Contact Point Address:
  James P. O'Callaghan, Ph.D., Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Mailstop L-3014, Morgantown, WV 26505
• Email:
  jdo5@cdc.gov
• CAS Registry Number:
  (-)-Physostigmine (CAS RN 57-47-6) ; Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2017
• Peer Reviewed:
  True
• Collection(s):
  National Institute for Occupational Safety and Health CDC Public Access
• 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 ]