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
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 pyrid...
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00182/full |
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| author | Geetha A. Shetty Geetha A. Shetty Geetha A. Shetty Bharathi Hattiangady Bharathi Hattiangady Bharathi Hattiangady Dinesh Upadhya Dinesh Upadhya Dinesh Upadhya Adrian Bates Adrian Bates Adrian Bates Sahithi Attaluri Sahithi Attaluri Bing Shuai Bing Shuai Bing Shuai Maheedhar Kodali Maheedhar Kodali Maheedhar Kodali Ashok K. Shetty Ashok K. Shetty Ashok K. Shetty |
| author_facet | Geetha A. Shetty Geetha A. Shetty Geetha A. Shetty Bharathi Hattiangady Bharathi Hattiangady Bharathi Hattiangady Dinesh Upadhya Dinesh Upadhya Dinesh Upadhya Adrian Bates Adrian Bates Adrian Bates Sahithi Attaluri Sahithi Attaluri Bing Shuai Bing Shuai Bing Shuai Maheedhar Kodali Maheedhar Kodali Maheedhar Kodali Ashok K. Shetty Ashok K. Shetty Ashok K. Shetty |
| author_sort | Geetha A. Shetty |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T20:57:41Z |
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| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-22T20:57:41Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b48ab336548b432792bf5f33fde852212022-12-21T18:12:54ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-06-011010.3389/fnmol.2017.00182268370Chronic 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 IllnessGeetha A. Shetty0Geetha A. Shetty1Geetha A. Shetty2Bharathi Hattiangady3Bharathi Hattiangady4Bharathi Hattiangady5Dinesh Upadhya6Dinesh Upadhya7Dinesh Upadhya8Adrian Bates9Adrian Bates10Adrian Bates11Sahithi Attaluri12Sahithi Attaluri13Bing Shuai14Bing Shuai15Bing Shuai16Maheedhar Kodali17Maheedhar Kodali18Maheedhar Kodali19Ashok K. Shetty20Ashok K. Shetty21Ashok K. Shetty22Research Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesResearch Service, Olin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System, TempleTX, United StatesInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple and College StationTX, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College StationTX, United StatesMemory 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.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00182/fullmitochondrial dysfunctionmemory and mood impairmentmitogen-activated protein kinasenuclear factor kappa bNF-E2-related factor 2oxidative stress |
| spellingShingle | Geetha A. Shetty Geetha A. Shetty Geetha A. Shetty Bharathi Hattiangady Bharathi Hattiangady Bharathi Hattiangady Dinesh Upadhya Dinesh Upadhya Dinesh Upadhya Adrian Bates Adrian Bates Adrian Bates Sahithi Attaluri Sahithi Attaluri Bing Shuai Bing Shuai Bing Shuai Maheedhar Kodali Maheedhar Kodali Maheedhar Kodali Ashok K. Shetty Ashok K. Shetty Ashok K. Shetty 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 Frontiers in Molecular Neuroscience mitochondrial dysfunction memory and mood impairment mitogen-activated protein kinase nuclear factor kappa b NF-E2-related factor 2 oxidative stress |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | mitochondrial dysfunction memory and mood impairment mitogen-activated protein kinase nuclear factor kappa b NF-E2-related factor 2 oxidative stress |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00182/full |
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