Organophosphate-induced neuroinflammation, with and without corticosterone pretreatment, is not due to acetylcholinesterase inhibition

Details

• Personal Author:
  Kelly KA ; Locker AR ; Michalovicz LT ; Miller DB ; O'Callaghan JP
• Description:
  Organophosphates (OP) are used worldwide in a variety of settings. Irreversible acetylcholinesterase inhibitors (AChEIs) are used as insecticides (chlorpyrifos (CPF)) and nerve agents (sarin, or surrogate diisopropyl fluorophosphate (DFP)). Reversible AChEIs have been used as a prophylactic as protection from nerve agent and pharmacologically for treatment of myasthenia gravis (pyridostigmine bromide (PB)) and glaucoma (physostigmine (PHY)). Exposure to AChEIs increases acetylcholinergic transmission resulting in salivation, lacrimation, urination, defecation (SLUD) symptoms, muscle rigidity, seizures, paralysis of the heart, and death. Lesser known effects of exposure to some AChEIs (e.g., DFP), paradoxically, include increases in levels of proinflammatory cytokines in the brain, effects exacerbated by chronic (4-7 days) pretreatment with the stress hormone, corticosterone (CORT). Here, we examined neuroinflammatory and AChE effects following peripheral exposure to different reversible and irreversible AChEIs [those that do and do not cross the blood brain barrier (BBB)] with and without CORT pretreatment in male C57BL/6J mice. Using qPCR, we found that the CNS acting irreversible compounds (DFP and CPF) and reversible compound physostigmine (PHY) produced altered levels of proinflammatory cytokines compared to saline treated controls, and further, that pretreatment with CORT augments these brain effects. Administration of the non-BBB crossing reversible AChEI, PB, alone, or following CORT pretreatment produces few inflammatory effects in the brain. Furthermore, irreversible (DFP and CPF) and reversible (PHY) CNS-acting AChEIs all produce decreases in AChE activity levels. Similar effects were not seen following PB exposure, consistent with a lack of brain penetrance. The protection against AChE activity loss and augmentation of neuroinflammation following pretreatment with CORT and subsequent exposure to AChEIs suggests that the neuroinflammation is not a product of AChEIs effect on cholinesterase activity in the brain. Instead, neuroinflammation seen following the exposure to CNS acting AChE inhibiting OPs, with and without CORT, likely is a result of organophosphorylation of yet to be identified protein targets in addition to ACHE. [Description provided by NIOSH]
• Subjects:
  Bromides Immune System Insecticides Nervous System Occupational Health Organophosphates Safety Toxicology
• Keywords:
  Acetylcholinesterase Biological Effects Chemical Warfare Agents Chlorpyrifos Cholinesterase Inhibitors Corticosteroids Cytokines Immune Reaction Nerve Function Neuropharmacology Neurotoxic Agents Organophosphorus Compounds Organophosphorus Insecticides Organophosphorus Pesticides Pesticides Pharmacology

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Louisiana ; OSHA Region 3 ; OSHA Region 6 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047811
• Citation:
  Toxicologist 2016 Mar; 150(1):450
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2016
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 55th Annual Meeting and ToxExpo, March 13-17, 2016, New Orleans, Louisiana
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:88b5e63644ec0cc2997d120d7d489291856acf750303ead804cb4c974f331239cca9068681736dd6830bfddaebc3385759d4e9bdeacf31ed97e41d6e83386d16
• Download URL:
  https://stacks.cdc.gov/view/cdc/202782/cdc_202782_DS1.pdf
• File Type:
  [PDF - 442.29 KB ]