A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Joshi, Utsav; Pearson, Andrew; Evans, James E.; Langlois, Heather; Saltiel, Nicole; Ojo, Joseph; Klimas, Nancy G.; Sullivan, Kimberly; Keegan, Andrew P.; Oberlin, Sarah; Darcey, Teresa; Cseresznye, Adam; Raya, Balaram; Paris, Daniel; Hammock, Bruce D.; Vasylieva, Natalia; Hongsibsong, Surat; Stern, Lawrence J.; Crawford, Fiona; Mullan, Michael; Abdullah, Laila

doi:10.1016/j.bbi.2019.07.015

Cited by 38 publications

(40 citation statements)

References 81 publications

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“…Increased autoantibodies of biomarkers NFP, tau, tubulin, and MBP, and neuronal cytoskeletal disruptions, including microtubule instability, axonal degeneration, and altered axonal transport, have been found in many cell and animal studies of toxicant-induced models of GWI [ 27 , 42 , 43 , 44 , 45 , 49 , 52 , 53 , 54 ]. We are only aware of the following prior studies, including our prior pilot study, showing increased autoantibodies in much smaller pilot studies of GW veteran blood samples [ 12 , 55 , 56 , 57 , 58 ]. To our knowledge, this is the first large, more definitive study to validate these prior animal, cell, and veteran studies in the blood of ill GW veterans compared with combined and separate healthy and symptomatic comparison groups.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

et al. 2020

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For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder. Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)). Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS). For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS. Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

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“…Consistent with the above ndings, studies on animal model of GWI also have found that insecticides such as N, N-diethyl-m-toluamide (DEET) and permethrin can cause chronic brain dysfunction, including decreasing adult hippocampal neurogenesis, over activation of neuro-in ammation, damaging the bloodbrain barrier, causing nerve cells death in the dentate gyrus and hypothalamus 4 . Brain dysfunction is typi ed by depression, anxiety and impaired cognition 5 .…”

Section: Introductionsupporting

confidence: 55%

Effects of minocycline on neuroinflammation, gut microbiome and hippocampal neurogenesis in rats with Gulf War Illness

Liu

Wang

et al. 2020

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Background Accumulating evidence suggests that deficits in neurogenesis, chronic inflammation and gut microbiome dysregulation contribute to the pathophysiology of Gulf War Illness (GWI). Minocycline has been demonstrated to be a potent neuroprotective agent and could regulate neuroinflammation. The present study intended to investigate whether treatment of minocycline maintain better cognition and mood function in a rat model of GWI and the potential mechanism. Methods Rats received 28 days of GWI-related chemical exposure and restraint stress, along with daily minocycline or vehicle treatment. Cognitive and mood function, neuroinflammation, neurogenesis and gut microbiota were detected. Results We found that minocycline treatment induced better cognitive and mood function in a GWI rat model, as indicated by open-field test, elevated plus maze test, novel object recognition test and forced swim test. Moreover, minocycline treatment reversed the altered gut microbiome, neuroinflammation and the decreased hippocampal neurogenesis of rats with GWI. Conclusion Taken together, our study indicated that minocycline treatment exerts better cognitive and mood function in GWI rat model, which is possible related to gut microbiota remodeling, restrained inflammation and enhanced hippocampal neurogenesis. These results may establish minocycline a potential prophylactic or therapeutic agent for the treatment of GWI.

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“…However, it is the long-term neurological symptoms associated with exposure to these compounds that harmonize with many of the long-lasting symptoms of GWI: fatigue, pain, mood disorders, cognitive and memory impairment ( Fukuda et al, 1998 ; Steele, 2000 ; Haley et al, 2001 ; Golomb, 2008 ; Sullivan et al, 2003 ; Maule et al, 2018 ). Furthermore, the similarity of these symptoms to those of sickness behavior, the adaptive behavioral response elicited by illnessor infection-induced neuroinflammation ( Dantzer and Kelley, 2007 ; Dantzer et al, 2008 ), has suggested that GWI is the result of an underlying chronic neuroimmune disorder; a hypothesis that has been supported by both preclinical animal ( O’Callaghan et al, 2015 ; Zakirova et al, 2016 ; Alhasson et al, 2017 ; Locker et al, 2017 ; Shetty et al, 2017 ; Ashbrook et al, 2018 ; Carreras et al, 2018 ; Kodali et al, 2018 ; Koo et al, 2018 ; Macht et al, 2018 , 2019 ; Miller et al, 2018 ; Hernandez et al, 2019 ; Joshi et al, 2019 ; Madhu et al, 2019 ; Michalovicz et al, 2019 ) and clinical studies ( Broderick et al, 2013 ; Parkitny et al, 2015 ; White et al, 2016 ; Coughlin, 2017 ; Abou-Donia et al, 2017 ; Georgopoulous et al, 2017 ; Alshelh et al, 2020 ). In spite of the fact that the ACh signaling facilitated by AChE inhibition is typically anti-inflammatory ( Pavlov et al, 2003 ; Pavlov and Tracey, 2005 ), several preclinical studies have directly shown a connection between GWI-relevant AChEI exposures and neuroinflammation ( Ojo et al, 2014 ; O’Callaghan et al, 2015 ; Locker et al, 2017 ; Ashbrook et al, 2018 ; Koo et al, 2018 ; Miller et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a significant number of exposure models have been developed that combine PB with other, non-AChEI, GW-relevant chemicals including: permethrin (PER) with or without stress ( Abdullah et al, 2011 ; Zakirova et al, 2015 ; Alhasson et al, 2017 ; Nizamutdinov et al, 2018 ; Seth et al, 2018 ; Joshi et al, 2019 ); PER and DEET with or without stress ( Abou-Donia et al, 1996 ; Abdel-Rahman et al, 2002 ; Abdullah et al, 2012 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Megahed et al, 2015 ; Pierce et al, 2016 ; Shetty et al, 2017 ; Carerras et al, 2018 ; Petrescu et al, 2018 ; Madhu et al, 2019 ); PER and CPF with or without DEET ( Ojo et al, 2014 ; Nutter et al, 2015 ; Cooper et al, 2016 , 2018 ; Flunker et al, 2017 ). The prominence of these mixtures in GWI models, which largely revolve around combined exposures with PER and DEET, stem from a recommendation in the report from the Institute of Medicine (US) Committee to Review the Health Consequences of Service During the Persian Gulf War (1995 ) and an initial study of these chemicals in a hen model ( Abou-Donia et al, 1996 ).…”

Section: Introductionmentioning

confidence: 99%

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

et al. 2020

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Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to “off-target”, non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder. This article is part of the special issue entitled ‘Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield’.

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A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Cited by 38 publications

References 81 publications

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

Effects of minocycline on neuroinflammation, gut microbiome and hippocampal neurogenesis in rats with Gulf War Illness

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

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