Pyridostigmine bromide suppresses neuroinflammation induced by DFP

Details

• Personal Author:
  Kelly KA ; Lasley SM ; Miller DB ; O'Callaghan JP ; Revitsky AR
• Description:
  Use of our Gulf War Illness (GWI) mouse model has shown that administration of diisopropyl fluorophosphate (DFP) results in neuroinflammatory responses involving multiple cytokines/chemokines. Paradoxically, pretreatment with the anti- inflammatory stress hormone corticosterone (CORT) exaggerates this response. Neuroinflammation in the CNS results in sickness behavior, a persistent element of GWI. Soldiers in the 1991 Gulf War were instructed to consume the reversible cholinesterase inhibitor pyridostigmine bromide (PB) when under threat of nerve agent exposure. Here, we investigated how exposure to PB alone and combined with our GWI model affected neuroinflammatory responses. Male C57BL6J mice acutely exposed to PB (3.0 mg/kg) or PB following 4 days of CORT (400 mg/L in the drinking water) showed no significant neuroinflammatory changes in most markers (TNF-alpha, OSM, IL-1beta, LIF, IL-6) and no signs of astrogliosis (no increases in GFAP) in the hippocampus and cortex, findings suggestive of a lack of underlying neural damage. Investigation of the effects of chronic PB treatment prior to DFP exposure revealed a general reduction of DFP-induced neuroinflammatory markers (IL-6, LIF, TNF-alpha, IL-1 beta, OSM), findings consistent with the expected competitive effects of a reversible inhibitor given prior to an irreversible inhibitor. PB pretreatment prior to chronic CORT and DFP exposure produced little to no suppression of neuroinflammatory responses. These results suggest that, unlike exposure to irreversible AChE inhibitors, exposure to PB, a reversible inhibitor, produces negligible proinflammatory effects on the CNS with no signs of neural injury. Furthermore, PB exposure prior to nerve agents, such as DFP, blunts neuroinflammatory responses, but this dampening effect of PB on neuroinflammation is not present when baseline cortisol levels are heightened. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Anti-Bacterial Agents Behavior Biological Warfare Agents Biomarkers Bromides Cholinesterase Inhibitors Chronic Disease Cytotoxins Endocrine System Environmental Monitoring Immune System Laboratories Mental Disorders Nervous System Nervous System Disorders Occupational Health Safety Toxicology

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• Keywords:
  Antibiotics Behavioral-disorders Biological-warfare-agents Brain-function Central-nervous-system-disorders Cholinesterase-inhibitors Chronic-inflammation Corticoids Cytotoxicity Dose-response Exposure-assessment Hormones Immune-reaction Laboratory-animals Laboratory-testing Mental-illness Military-personnel Neurotoxicity Physiological-stress Pretreatment Stress

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; Illinois ; OSHA Region 3 ; OSHA Region 5 ; OSHA Region 9 ; 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:
  456-457
• Volume:
  144
• Issue:
  1
• NIOSHTIC Number:
  nn:20045995
• Citation:
  Toxicologist 2015 Mar; 144(1):456-457
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Pyridostigmine bromide (CAS RN 101-26-8)
• Federal Fiscal Year:
  2015
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 54th Annual Meeting and ToxExpo, March 22-26, 2015, San Diego, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8d73bb209935e55dbf4bd1f8bd5f3c0cca97d71525cd3fffa6cc480679fa6df6fb12fa91691e35a27d75e2c64de0f287630da785b48d03dd622296761fdffd7e
• Download URL:
  https://stacks.cdc.gov/view/cdc/201194/cdc_201194_DS1.pdf
• File Type:
  [PDF - 236.22 KB ]