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Resetting homeostasis in Gulf War Illness, a computational biology hypothesis tested in a translational mouse model.

Kelly KA; Michalovicz LT; Miller JV; Broderick G; Rice M; Craddock TJ; Fletcher MA; Morris M; Klimas N; Miller DB; O'Callaghan JP
Toxicologist 2017 Mar; 156(1):171
Gulf War Illness (GWI) is a multi-symptom disorder diagnosed by phenotype including: persistent headaches, chronic fatigue, memory loss, confusion, skin and gastrointestinal problems. These features are characteristic of persistent sickness behavior, which results from underlying neuroinflammation. Current treatment of GWI aims to manage symptoms as conventional treatments have failed to effectively treat the underlying dysfunction associated with GWI. Under the extreme conditions of deployment and possible exposure to toxic agents, the normal neuroendocrine-immune control system may have been overwhelmed, resulting in re-tuning of the system to a new homeostasis. In an effort to promote remission in GWI patients, a computational/systems biology approach revealed a two-step therapeutic intervention in which TH1 inflammatory cytokine inhibition followed by glucocorticoid receptor inhibition may not only improve symptoms, but also reset homeostasis. Here, we tested the therapeutic potential of this two-step reset in an established neuroinflammatory model of GWI. Animals were treated with corticosterone (CORT; 200mg/L in 0.6% ethanol) drinking water for 7 days followed by a single injection of diisopropyl fluorophosphates (DFP; 4mg/kg, i.p.). Mice were then exposed to CORT drinking water for 7 days every other week for a total of 5 weeks followed by an immune challenge, LPS (0.5mg/kg, s.c.). The therapeutic intervention was given during the 2nd CORT exposure with Enbrel (5mg/kg, i.p.; TNFa antagonist) given on the 3rd day of CORT and Mifepristone (20mg/kg, i.p.; glucocorticoid antagonist) given on the 5th day. Mice were sacrificed 6 hours after the LPS challenge and brain cytokine expression was measured by qPCR. The CORT-DFP model of GWI produces a profound neuroinflammatory response to the LPS inflammatory challenge (51 +/- 8% increase across 6 markers over CORT priming). Reset therapy was able to markedly reduce cytokine expression in cortex (31 +/- 8%) and hippocampus (30 +/- 6%), indicating a strong therapeutic potential for this drug combination in GWI. Further work is being done to evaluate the effectiveness of this combination at later time points in mice and implement this potential therapeutic intervention in patients.
Toxicology; Models; Military personnel; Health effects; Neurological disorders; Neurological reactions; Immune reaction; Behavior patterns; Endocrine system disorders; Therapeutic agents; Cytokines; Intervention; Corticoids; Medical treatment; Translational research; Analytical models; Analytical processes; Laboratory animals; Laboratory testing; Exposure assessment; Immune system; Exposure levels; Brain matter; Drug therapy; Brain function
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The Toxicologist. Society of Toxicology 56th Annual Meeting and ToxExpo, March 12-16, 2017, Baltimore, Maryland
Page last reviewed: May 11, 2023
Content source: National Institute for Occupational Safety and Health Education and Information Division