Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness

Abstract

Memory and mood dysfunction are the key symptoms of Gulf war illness (GWI), a lingering multi-symptom ailment afflicting >200,000 veterans who served in the Persian Gulf War-1. Research probing the source of the disease has demonstrated that concomitant exposures to anti-nerve gas agent pyridostigmine bromide (PB), pesticides, and war-related stress are among the chief causes of GWI. Indeed, exposures to GWI-related chemicals (GWIR-Cs) and mild stress in animal models cause memory and mood impairments alongside reduced neurogenesis and chronic low-level inflammation in the hippocampus. In the current study, we examined whether exposure to GWIR-Cs and stress causes chronic changes in the expression of genes related to increased oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus. We also investigated whether GWI is linked with chronically increased activation of Nrf2 (a master regulator of antioxidant response) in the hippocampus, and inflammation and enhanced oxidative stress at the systemic level. Adult male rats were exposed daily to low-doses of PB and pesticides (DEET and permethrin), in combination with 5 min of restraint stress for 4 weeks. Analysis of the hippocampus performed 6 months after the exposure revealed increased expression of many genes related to oxidative stress response and/or antioxidant activity (Hmox1, Sepp1, and Srxn1), reactive oxygen species metabolism (Fmo2, Sod2, and Ucp2) and oxygen transport (Ift172 and Slc38a1). Furthermore, multiple genes relevant to mitochondrial respiration (Atp6a1, Cox6a1, Cox7a2L, Ndufs7, Ndufv1, Lhpp, Slc25a10, and Ucp1) and neuroinflammation (Nfkb1, Bcl6, Csf2, IL6, Mapk1, Mapk3, Ngf, N-pac, and Prkaca) were up-regulated, alongside 73–88% reduction in the expression of anti-inflammatory genes IL4 and IL10, and nuclear translocation and increased expression of Nrf2 protein. These hippocampal changes were associated with elevated levels of pro-inflammatory cytokines and chemokines (Tnfa, IL1b, IL1a, Tgfb, and Fgf2) and lipid peroxidation byproduct malondialdehyde in the serum, suggesting the presence of an incessant systemic inflammation and elevated oxidative stress. These results imply that chronic oxidative stress, inflammation, and mitochondrial dysfunction in the hippocampus, and heightened systemic inflammation and oxidative stress likely underlie the persistent memory and mood dysfunction observed in GWI.

Minocycline Alleviate A Rat Model Of Gulf War Illness Via Altering Gut Microbiome, Attenuating Neuroinflammation And Enhancing Hippocampal Neurogenesis

“…Especially, neuroin ammation is one of the most essential factors in the progression of GWI. As previous reports, excessive neuroin ammation presented in veterans suffering from GWI and also observed in animal model of GWI 21,41 . Part of serum proteins associated with in ammation were signi cantly increased in veterans suffering from GWI, including interleukin 6, C-reactive protein, matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) 42,43 .…”

Trilobatin Protects Against Oxidative Injury in Neuronal PC12 Cells Through Regulating Mitochondrial ROS Homeostasis Mediated by AMPK/Nrf2/Sirt3 Signaling Pathway

“…When the cell is in an oxidative stress condition, active sites of cysteine residues of Keap-1 were oxidized, thereby prevented Keap-1 from bonding with Nrf2. Then, Nrf2 translocates into the nucleus and bonds to ARE including HO-1 and NQO-1, which are the crucial genes in the brain and is activated by Nrf2 to protect against neurons cell injury (Shetty et al, 2017 ). We thus focused on the role of Nrf2 in-depth.…”

Gulf war illness-related chemicals increase CD11b/c+ monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model

“…It was demonstrated that GWI-related chemicals can cause chronic oxidative stress, mitochondrial dysfunction and ultimately inflammation of certain areas of the brain, in association with elevated oxidative stress and inflammation at the systemic level 9 . Aspects of mood change and memory impairment due to exposure to GWI-related chemicals were also demonstrated in animal models of GWI 7,10 .…”