Ampakine CX546 Ameliorates Gulf War Agents Exposure and Stress-Induced Exosomal HMGB1 That Causes Neurological Ailment in Experimental Gulf War Illness

Details

• Personal Author:
  Albadrani MS ; Bose D ; Chatterjee S ; Horner RD ; Janulewicz Lloyd P ; Kimono D ; Mondal A ; O'Callaghan JP ; Saha P ; Sarkar S ; Seth RK ; Sullivan K
• Description:
  Gulf War Illness (GWI) is a medically unexplained, multisymptomatic condition that includes chronic pain, gastrointestinal and neuroinflammation, and cognitive difficulties. Exposure to Gulf War (GW) agents pyridostigmine bromide (PB) and permethrin (Per), and war theater stress were key contributors to the etiology of GWI post-deployment to the Persian GW. In this study, we examined the role of circulatory exosomal high mobility group box-1 (HMGB1) protein in neuroinflammation, neuroimmunotoxicity, and neuroplasticity in the mouse model of GWI. Here, we used an established mouse model of GWI. The C57BL/6 mice were exposed to GW agents (PB+Per) along with restraint stress for one week. Results show that GW agent exposure along with stress causes exosomal biogenesis and HMGB1 expression in the small intestine and concurrently increase circulatory exosome loaded with HMGB1. Data also show decrease Zonal Occludin-1 (ZO1) and Claudin-1 mRNA expression, and serum albumin accumulation in frontal cortex suggests blood-brain barrier (BBB) integrity loss that enables entry of circulatory exosomal HMGB1 in the brain. Increase HMGB1 in both the frontal cortex and hippocampus activate microglia (M1 phenotype), thus induces an inflammatory response. We observed that HMGB1 induced neuroinflammation suppress brain-derived neurotropic factor (BDNF) and thus causing neuroplastic and cognitive impairment. The GW agents exposed mice co-treated with exosome inhibitor (Nexinhib20), or glutamate activator (ampakine, CX546) show improvement in BBB integrity, neuroinflammation, neuroplasticity, and cognitive function. In summary, our findings suggest that the circulatory exosomal HMGB1 plays a key role in GWI pathogenesis, and Nexinhib 20 and CX546 might be promising therapeutics in GWI. [Description provided by NIOSH]
• Subjects:
  Albumins Animals Blood Immune System Laboratories Nervous System Nervous System Diseases Occupational Health Safety Toxicology
• Keywords:
  Albumin Animal Studies Blood Serum Brain Matter Cellular Function Cellular Reactions Cell Wall Permeability Central Nervous System Circulatory System Cognitive Function Endothelial Cells Exposure Assessment Gene Expression Immune Reaction Immunologic Disorders Intestinal Tissue Laboratory Animals Laboratory Testing Military Personnel Models Molecular Signaling Neurological Disorders Neurological Reactions Neutrophils Proteins Ribonucleic Acids RNA Stress

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; Massachusetts ; OSHA Region 1 ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 9 ; South Carolina ; 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:
  174
• Issue:
  1
• NIOSHTIC Number:
  nn:20058919
• Citation:
  Toxicologist 2020 Mar; 174(1):204
• CAS Registry Number:
  Permethrin (CAS RN 52645-53-1) ; Pyridostigmine bromide (CAS RN 101-26-8)
• Federal Fiscal Year:
  2020
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 59th Annual Meeting and ToxExpo, March 15-19, 2020, Anaheim, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d1e36032742b9564b8808f35675c7163ff25bb746f972a965eff277971bab13bf488e1e4e63a62f232b3031d586180bd979ee191f93254cd45246a04dbb22088
• Download URL:
  https://stacks.cdc.gov/view/cdc/223278/cdc_223278_DS1.pdf
• File Type:
  [PDF - 522.42 KB ]