Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness

Abstract

Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse model to identify biological processes that are relevant to the chronic symptoms of GWI. Three-month old male C57BL6 mice were exposed for 10days to GW agents (pyridostigmine bromide and permethrin). Barnes Maze testing conducted at 15- and 16-months post-exposure revealed learning and memory impairment. Immunohistochemical analyses showed astroglia and microglia activation in the hippocampi of exposed mice. Proteomic studies identified perturbation of mitochondria function and metabolomics data showed decreases in the Krebs cycle compounds, lactate, β-hydroxybutyrate and glycerol-3 phosphate in the brains of exposed mice. Lipidomics data showed decreases in fatty acids, acylcarnitines and phospholipids, including cardiolipins in the brains of exposed mice. Pilot biomarker studies showed that plasma from exposed mice and veterans with GWI had increases in odd-chain, and decreases in long-chain, acylcarnitines compared to their respective controls. Very long-chain acylcarnitines were decreased in veterans with GWI compared to controls. These studies suggest that mitochondrial lipid disturbances might be associated with GWI and that further investigation is required to determine its role in the pathophysiology of this illness. Targeting mitochondrial function may provide effective therapies for GWI, and that lipid abnormalities could serve as biomarkers of GWI.

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

“…A study by Koslik et al (2014) demonstrated mitochondrial dysfunction in the calf muscle of patients with GWI. Another study using a mouse model of GWI showed decreased levels of mitochondrial lipids in the brain, implying the reduced activity of electron transport chain (Abdullah et al, 2016), which contradicts the hyperactive mitochondrial respiration suggested by the current findings. The discrepancy between the studies could be attributed to the different time-points of investigation (i.e., at 15–16 months post-exposure in Abdullah et al, 2016 vis-à-vis 6 months post-exposure in the current study, respectively).…”

“…Another study using a mouse model of GWI showed decreased levels of mitochondrial lipids in the brain, implying the reduced activity of electron transport chain (Abdullah et al, 2016), which contradicts the hyperactive mitochondrial respiration suggested by the current findings. The discrepancy between the studies could be attributed to the different time-points of investigation (i.e., at 15–16 months post-exposure in Abdullah et al, 2016 vis-à-vis 6 months post-exposure in the current study, respectively). It is plausible that mitochondrial electron transport chain initially responds to neurotoxic exposure with hyperactivity, following which the generation of increased amounts of ROS, damages the electron transport chain over a period of time, eventually leading to its reduced activity.…”

“…This study provided first evidence that exposure to GWIR-Cs and stress leads to chronic oxidative stress, mitochondrial dysfunction, Nrf2 activation, and inflammation in the hippocampus, a region of the brain important for learning, memory, and mood but showing persistent impairment in animal models of GWI (Parihar et al, 2013; Hattiangady et al, 2014; Zakirova et al, 2015; Abdullah et al, 2016). Moreover, these adverse alterations in the hippocampus were not seen in isolation, but rather were associated with systemic inflammation and oxidative stress.…”

“…It is plausible that mitochondrial electron transport chain initially responds to neurotoxic exposure with hyperactivity, following which the generation of increased amounts of ROS, damages the electron transport chain over a period of time, eventually leading to its reduced activity. Additionally, exposure of animals to much higher doses of PB and PM by Abdullah et al (2016) than doses used in the current study may have played a role.…”

APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer’s Disease

“…The Folch extraction of serum and plasma samples was performed as previously described [66-68] using the Folch method [69] following an addition of di-14:0 fatty acid (FA) containing PC and PE (Matreya, Pleasant Gap, PA), di-16:0 PI, and 14:0 LPC (Avanti, Albaster, AL) as internal standards. High-pressure liquid chromatography (HPLC) was achieved using a 1mm ID x 10 cm column containing Pinnacle II 3 μm silica particles (Restek, Bellefonte, PA, USA).…”