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The Neuroinflammatory Phenotype in a Mouse Model of Gulf War Illness is Unrelated to Brain Regional Levels of Acetylcholine as Measured by Quantitative HILIC-UPLC-MS/MS.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2018 Oct 01; Vol. 165 (2), pp. 302-313. - Publication Year :
- 2018
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Abstract
- Many veterans of the 1991 Persian Gulf War (GW) returned with a chronic multisymptom illness that has been termed Gulf War Illness (GWI). Previous GWI studies have suggested that exposure to acetylcholinesterase inhibitors (AChEIs) in theater, such as sarin and/or pesticides, may have contributed to the symptomatology of GWI. Additionally, concomitant high physiological stress experienced during the war may have contributed to the initiation of the GWI phenotype. Although inhibition of AChE leading to accumulation of acetylcholine (ACh) will activate the cholinergic anti-inflammatory pathway, the signature symptomatology of GWI has been shown to be associated with neuroinflammation. To investigate the relationship between ACh and neuroinflammation in discrete brain regions, we used our previously established mouse model of GWI, which combines an exposure to a high physiological stress mimic, corticosterone (CORT), with GW-relevant AChEIs. The AChEIs used in this study were diisopropyl fluorophosphate (DFP), chlorpyrifos oxon (CPO), and physostigmine (PHY). After AChEI exposure, ACh concentrations for cortex (CTX), hippocampus (HIP), and striatum (STR) were determined using hydrophilic interaction liquid chromatography with ultraperformance liquid chromatography-tandem-mass spectrometry (MS/MS). CORT pretreatment ameliorated the DFP-induced ACh increase in HIP and STR, but not CTX. CORT pretreatment did not significantly alter ACh levels for CPO and PHY. Further analysis of STR neuroinflammatory biomarkers revealed an exacerbated CORT + AChEI response, which does not correspond to measured brain ACh. By utilizing this new analytical method for discrete brain region analysis of ACh, this work suggests the exacerbated neuroinflammatory effects in our mouse model of GWI are not driven by the accumulation of brain region-specific ACh.
- Subjects :
- Acetylcholine metabolism
Acetylcholinesterase metabolism
Animals
Brain drug effects
Brain metabolism
Cholinesterase Inhibitors toxicity
Chromatography, High Pressure Liquid
Corticosterone pharmacology
Inflammation
Male
Mice, Inbred C57BL
Persian Gulf Syndrome metabolism
Phenotype
Stress, Physiological drug effects
Tandem Mass Spectrometry
Acetylcholine analysis
Brain immunology
Cytokines metabolism
Disease Models, Animal
Persian Gulf Syndrome immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 165
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 29846716
- Full Text :
- https://doi.org/10.1093/toxsci/kfy130