Propranolol as a Novel Treatment for Gulf War Illness in a Preclinical Mouse Model

Details

• Personal Author:
  Kelly KA ; Michalovicz LT ; Miller DB ; O'Callaghan JP ; Sullivan K
• Description:
  Gulf War Illness (GWI) is a multi-symptom, neuroimmune-based disorder that presents with features similar to sickness behavior. Unfortunately, current treatments for GWI tend to focus on managing symptoms as opposed to addressing the underlying cause of the illness. Using a preclinical mouse model, we have found that GWI is associated with an exacerbated neuroinflammatory response to immune challenge, like lipopolysaccharide (LPS) exposure, and the activation of microglia. Interestingly, beta-adrenergic antagonism has been found to inhibit microglial activation and its associated release of inflammatory cytokines. Here, we tested the therapeutic potential of the beta-blocker propranolol in our established mouse model of GWI. In this model, mice are exposed to the stress hormone corticosterone (CORT; 200 mg/L) in the drinking water for 7 days followed by a single injection of diisopropyl fluorophosphate (DFP; 4 mg/kg, i.p.) to model the "in theater" conditions of high physiological stress and potential nerve agent exposure. This is then followed by periodic administration of CORT for 7 days every other week to a total of 5 weeks with a systemic LPS challenge (0.5 mg/kg, s.c.) on the final day. Propranolol (20 mg/kg, i.p.) was given during or outside of CORT exposure. Mice were sacrificed 6 hours after LPS challenge and brain cytokine mRNA expression was evaluated by qPCR. We found that propranolol significantly reduced the neuroinflammation instigated by the GWI exposure model when given during CORT exposure. In particular, treatment reduced cytokine expression in the GWI exposure group to levels comparable to CORT+LPS, which models a normal response to inflammatory challenge. These initial studies indicate the potential for propranolol to treat the underlying neuroinflammation associated with GWI and to return veterans to a healthy neuroimmune functional state. [Description provided by NIOSH]
• Subjects:
  Behavior Endocrine System Environmental Exposure Immune System Laboratories Lipids Nervous System Nervous System Diseases Occupational Health Safety Toxicology

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• Keywords:
  Analytical Models Behavior Patterns Cellular Reactions Corticosteroids Cytokines Dose Response Exposure Assessment Exposure Levels Hormones Immunologic Disorders Laboratory Animals Laboratory Testing Lipopolysaccharide Medical Treatment Medicinal Chemicals Military Personnel Neurological Disorders Neurotoxic Agents Physiological Stress Ribonucleic Acids RNA Therapeutic Agents

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; Massachusetts ; OSHA Region 1 ; 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:
  80
• Volume:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20054891
• Citation:
  Toxicologist 2019 Mar; 168(1):80
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Propranolol (CAS RN 525-66-6)
• Federal Fiscal Year:
  2019
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, Maryland
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:acceb31eefc3d829c511d754d0fef6f798c0c2efc8bba8e63fdf330395d70401fdfab357e8efad8597d89851619f9434dbea6665deb308b24b38c566200da3c2
• Download URL:
  https://stacks.cdc.gov/view/cdc/217304/cdc_217304_DS1.pdf
• File Type:
  [PDF - 859.80 KB ]