NeuroMolecular Medicine

, Volume 13, Issue 4, pp 275–288 | Cite as

Proteomic CNS Profile of Delayed Cognitive Impairment in Mice Exposed to Gulf War Agents

  • Laila Abdullah
  • Gogce Crynen
  • Jon Reed
  • Alex Bishop
  • John Phillips
  • Scott Ferguson
  • Benoit Mouzon
  • Myles Mullan
  • Venkatarajan Mathura
  • Michael Mullan
  • Ghania Ait-Ghezala
  • Fiona Crawford
Original Paper

Abstract

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.

Keywords

Cognitive impairment Proteomic Astrogliosis Gulf War illness 

References

  1. Abdel-Rahman, A., Shetty, A. K., & Abou-Donia, M. B. (2002). Disruption of the blood-brain barrier and neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf-War syndrome. Neurobiology of Diseases, 10, 306–326.CrossRefGoogle Scholar
  2. Abdel-Rahman, A., Abou-Donia, S., El-Masry, E., Shetty, A., & Abou-Donia, M. (2004). Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum. Journal of Toxicology and Environment Health A, 267, 163–192.CrossRefGoogle Scholar
  3. Abou-Donia, M. B., Dechkovskaia, A. M., Goldstein, L. B., Abdel-Rahman, A., Bullman, S. L., & Khan, W. A. (2004). Co-exposure to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity. Pharmacology, Biochemistry and Behavior, 77, 253–262.CrossRefGoogle Scholar
  4. Aguilar, R., Gil, L., Flint, J., Gray, J. A., Dawson, G. R., Driscoll, P., et al. (2002). Learned fear, emotional reactivity and fear of heights: A factor analytic map from a large F(2) intercross of Roman rat strains. Brain Research Bulletin, 57, 17–26.PubMedCrossRefGoogle Scholar
  5. Aquilonius, S. M., Eckernäs, S. A., Hartvig, P., Lindström, B., Osterman, P. O., & Stålberg, E. (1983). Clinical pharmacology of pyridostigmine and neostigmine in patients with myasthenia gravis. Journal of Neurology, Neurosurgery and Psychiatry, 46, 929–935.CrossRefGoogle Scholar
  6. Bansal, I., Waghmare, C. K., Anand, T., Gupta, A. K., & Bhattacharya, B. K. (2009). Differential mRNA expression of acetylcholinesterase in the central nervous system of rats with acute and chronic exposure of sarin and physostigmine. Journal of Applied Toxicology, 29, 386–394.PubMedCrossRefGoogle Scholar
  7. Bantscheff, M., Boesche, M., Eberhard, D., Matthieson, T., Sweetman, G., & Kuster, B. (2008). Robust and sensitive iTRAQ quantification on an LTQ Orbitrap mass spectrometer. Molecular and Cellular Proteomics, 7, 1702–1713.PubMedCrossRefGoogle Scholar
  8. Bayés, A., & Grant, S. G. (2009). Neuroproteomics: Understanding the molecular organization and complexity of the brain. Nature Reviews Neuroscience, 10, 635–646.PubMedCrossRefGoogle Scholar
  9. Binns, J. H., Barlow, C., Bloom, F. E., Clauw, D. J., Golomb, B. A., Graves, J. C. et al. (Research Advisory Committee on Gulf War Veterans’ Illnesses). (2008). Gulf War Illness and the health of Gulf War Veterans. Washington, DC: Department of Veterans Affairs. http://www1.va.gov/rac-gwvi/.
  10. Blanchard, D. C., Griebel, G., & Blanchard, R. J. (2001). Mouse defensive behaviors: Pharmacological and behavioral assays for anxiety and panic. Neuroscience and Biobehavioral Reviews, 25, 205–218.PubMedCrossRefGoogle Scholar
  11. Blaylock, B. L., Abdel-Nasser, M., McCarty, S. M., Knesel, J. A., Tolson, K. M., Ferguson, P. W., et al. (1995). Suppression of cellular immune responses in BALB/c mice following oral exposure to permethrin. Bulletin of Environmental Contamination and Toxicology, 54, 768–774.PubMedCrossRefGoogle Scholar
  12. Bondolfi, B. L., Calhoun, M., Ermini, F., Kuhn, H. G., Wiederhold, K. H., Walker, L., et al. (2002). Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice. Journal of Neuroscience, 22, 515–522.PubMedGoogle Scholar
  13. Chaney, L. A., Rockhold, R. W., Mozingo, J. R., Hume, A. S., & Moss, J. I. (1997). Potentiation of pyridostigmine bromide toxicity in mice by selected adrenergic agents and caffeine. Veterinary and Human Toxicology, 39, 214–219.PubMedGoogle Scholar
  14. Chiasserini, D., Parnetti, L., Andreasson, U., Zetterberg, H., Giannandrea, D., Calabresi, P., et al. (2010). CSF Levels of heart fatty acid binding protein are altered during early phases of Alzheimer’s disease. Journal of Alzheimer’s Disease, 22, 1281–1288.PubMedGoogle Scholar
  15. Corbel, V., Stankiewicz, M., Bonnet, J., Grolleau, F., Hougard, J. M., & Lapied, B. (2006). Synergism between insecticides permethrin and propoxur occurs through activation of presynaptic muscarinic negative feedback of acetylcholine release in the insect central nervous system. Neurotoxicology, 27, 508–519.PubMedCrossRefGoogle Scholar
  16. Crawford, F., Wood, M., Ferguson, S., Mathura, V., Gupta, P., Humphrey, J., et al. (2009). Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury. Neuroscience, 159, 1349–1362.PubMedCrossRefGoogle Scholar
  17. Dagvajantsan, B., Aoki, M., Warita, H., Suzuki, N., & Itoyama, Y. (2008). Up-regulation of insulin-like growth factor-II receptor in reactive astrocytes in the spinal cord of amyotrophic lateral sclerosis transgenic rats. Tohoku Journal of Experimental Medicine, 214, 303–310.PubMedCrossRefGoogle Scholar
  18. David, A. S., Farrin, L., Hull, L., Unwin, C., Wessely, S., & Wykes, T. (2002). Cognitive functioning and disturbances of mood in UK veterans of the Persian Gulf War: A comparative study. Psychological Medicine, 32, 1357–1370.PubMedCrossRefGoogle Scholar
  19. De Keyser, J., Mostert, J. P., & Koch, M. W. (2008). Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. Journal of the Neurological Sciences, 267, 3–16.PubMedCrossRefGoogle Scholar
  20. Diel, F., Detscher, M., Borck, H., Schrimpf, D., Diel, E., & Hoppe, H. W. (1998). Effects of permethrin on human basophils and lymphocytes in vitro. Inflammation Research, 47, S11–S12.PubMedCrossRefGoogle Scholar
  21. Dodd, C. A., & Klein, B. G. (2009). Pyrethroid and organophosphate insecticide exposure in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson’s disease: an immunohistochemical analysis of tyrosine hydroxylase and glial fibrillary acidic protein in dorsolateral striatum. Toxicology and Industrial Health, 25, 25–39.PubMedCrossRefGoogle Scholar
  22. Erdfelder, E., Faul, F., & Buchner, A. (1996). GPOWER: A general power analysis program. Behavior Research Methods, Instruments and Computers, 28, 1–11.CrossRefGoogle Scholar
  23. Faulkner, J. R., Herrmann, J. E., Woo, M. J., Tansey, K. E., Doan, N. B., & Sofroniew, M. V. (2004). Reactive astrocytes protect tissue and preserve function after spinal cord injury. Journal of Neuroscience, 24, 2143–2155.PubMedCrossRefGoogle Scholar
  24. Friedman, A., Kaufer, D., Shemer, J., Hendler, I., Soreq, H., & Tur-Kaspa, I. (1996). Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Medicine, 2, 1382–1385.PubMedCrossRefGoogle Scholar
  25. Golier, J. A., Legge, J., & Yehuda, R. (2006). The ACTH response to dexamethasone in Persian Gulf War veterans. Annals of the New York Academy of Sciences, 1071, 448–453.PubMedCrossRefGoogle Scholar
  26. Gray, G. C., Kaiser, K. S., Hawksworth, A. W., Hall, F. W., & Barrett-Connor, E. (1999). Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans. The American journal of Tropical and Medical Hygienic, 60, 758–766.Google Scholar
  27. Grimm, R., Schicknick, H., Riede, I., Gundelfinger, E. D., Herdegen, T., Zuschratter, W., et al. (1997). Suppression of c-fos induction in rat brain impairs retention of a brightness discrimination reaction. Learning and Memory, 3, 402–413.PubMedCrossRefGoogle Scholar
  28. Haley, R. W., Vongpatanasin, W., Wolfe, G. I., Bryan, W. W., Armitage, R., Hoffmann, R. F., et al. (2004). Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. American Journal of Medicine, 117, 469–478.PubMedCrossRefGoogle Scholar
  29. Hilborne, L. H., Golomb, B. A., Marshall, G. N., Davis, L. M., Sherbourne, C. D., Augerson, W., et al. (2005). Examining possible causes of Gulf War Illness: RAND policy investigations and reviews of the scientific literature. Santa Monica, CA: RAND Corporation. http://www.rand.org/pubs/research_briefs/RB7544.
  30. Hill, E. G., Schwacke, J. H., Comte-Walters, S., Slate, E. H., Oberg, A. L., Eckel-Passow, J. E., et al. (2008). A statistical model for iTRAQ data analysis. Journal of Proteome Research, 7, 3091–3101.PubMedCrossRefGoogle Scholar
  31. Hoy, J. B., Cody, B. A., Karlix, J. L., Schmidt, C. J., Tebbett, I. R., Toffollo, S., et al. (1999). Pyridostigmine bromide alters locomotion and thigmotaxis of rats: Gender effects. Pharmacology, Biochemistry and Behavior, 63, 401–406.CrossRefGoogle Scholar
  32. Hoy, J. B., Cornell, J. A., Karlix, J. L., Tebbett, I. R., & van Haaren, F. (2000). Repeated coadministrations of pyridostigmine bromide, DEET, and permethrin alter locomotor behavior of rats. Veterinary and Human Toxicology, 42, 72–76.PubMedGoogle Scholar
  33. Hue, B., & Mony, L. (1987). Actions of deltamethrin and tralomethrin on cholinergic synaptic transmission in the central nervous system of the cockroach (Periplaneta americana). Comparative Biochemistry and Physiology Part C, 86, 349–352.CrossRefGoogle Scholar
  34. Institute of Medicine. (2010). Gulf War and Health, volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press.Google Scholar
  35. Katz, M. H. (2006). Multivariable analysis, a practical guide. Cambridge: Cambridge University Press.CrossRefGoogle Scholar
  36. Kroenke, K., Koslowe, P., & Roy, M. (1998). Symptoms in 18, 495 Persian Gulf War veterans. Latency of onset and lack of association with self-reported exposures. Journal of Occupational and Environmental Medicine, 40, 520–528.PubMedCrossRefGoogle Scholar
  37. Lamproglou, I., Barbier, L., Diserbo, M., Fauvelle, F., Fauquette, W., & Amourette, C. (2009). Repeated stress in combination with pyridostigmine Part I: Long-term behavioural consequences. Behavioural Brain Research, 197, 301–310.PubMedCrossRefGoogle Scholar
  38. Lue, L.F., Kuo, Y. M., Beach, T., Walker, D. G. (2010). Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Molecular Neurobiology, 41, 115–28. Epub 2010 Mar 3.Google Scholar
  39. Maruff, P., & Falleti, M. (2005). Cognitive function in growth hormone deficiency and growth hormone replacement. Hormone Research, 64, 100–108.PubMedCrossRefGoogle Scholar
  40. Masuda, T., Tomita, M., & Ishihama, Y. (2008). Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. Journal of Proteome Research, 7(2), 731–740.PubMedCrossRefGoogle Scholar
  41. Menon, P. M., Nasrallah, H. A., Reeves, R. R., & Ali, J. A. (2004). Hippocampal dysfunction in Gulf War Syndrome A proton MR spectroscopy study. Brain Research, 1009, 189–194.PubMedCrossRefGoogle Scholar
  42. Motohashi, K., Yamamoto, Y., Shioda, N., Kondo, H., Owada, Y., & Fukunaga, K. (2009). Role of heart-type fatty acid binding protein in the brain function. Yakugaku Zasshi., 129, 191–195.PubMedCrossRefGoogle Scholar
  43. Murphy, E. J., Owada, Y., Kitanaka, N., Kondo, H., & Glatz, J. F. (2005). Brain arachidonic acid incorporation is decreased in heart fatty acid binding protein gene-ablated mice. Biochemistry, 44, 6350–6360.PubMedCrossRefGoogle Scholar
  44. Myer, D. J., Gurkoff, G. G., Lee, S. M., Hovda, D. A., & Sofroniew, M. V. (2006). Essential protective roles of reactive astrocytes in traumatic brain injury. Brain, 129, 2761–2772.PubMedCrossRefGoogle Scholar
  45. Peacock, M. D., Morris, M. J., Houghland, M. A., Anders, G. T., & Blanton, H. M. (1997). Sleep apnea-hypopnea syndrome in a sample of veterans of the Persian Gulf War. Military Medicine, 162, 249–251.PubMedGoogle Scholar
  46. Peden-Adams, M. M., Dudley, A. C., EuDaly, J. G., Allen, C. T., Gilkeson, G. S., & Keil, D. E. (2004). Pyridostigmine bromide (PYR) alters immune function in B6C3F1 mice. Immunopharmacology and Immunotoxicology, 26, 1–15.PubMedCrossRefGoogle Scholar
  47. Pittman, J. T., Dodd, C. A., & Klein, B. G. (2003). Immunohistochemical changes in the mouse striatum induced by the pyrethroid insecticide permethrin. International Journal of Toxicology, 22, 359–370.PubMedGoogle Scholar
  48. Prater, M. R., Blaylock, B. L., & Holladay, S. D. (2005). Combined dermal exposure to permethrin and cis-urocanic acid suppresses the contact hypersensitivity response in C57BL/6N mice in an additive manner. Journal of Photochemistry and Photobiology B: Biology, 78, 29–34.CrossRefGoogle Scholar
  49. Punareewattana, K., Smith, B. J., Blaylock, B. L., Longstreth, J., Snodgrass, H. L., Gogal, R. M., et al. (2001). Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice. Food and Chemical Toxicology, 39, 133–139.PubMedCrossRefGoogle Scholar
  50. Ray, D. E., & Fry, J. R. (2006). A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacology and Therapeutics, 111(1), 174–193.PubMedCrossRefGoogle Scholar
  51. Schumm, W. R., Reppert, E. J., Jurich, A. P., Bollman, S. R., Webb, F. J., Castelo, C. S., et al. (2002). Pyridostigmine bromide and the long-term subjective health status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychological Reports, 90, 707–721.PubMedGoogle Scholar
  52. Skowera, A., Hotopf, M., Sawicka, E., Varela-Calvino, R., Unwin, C., Nikolaou, V., et al. (2004). Cellular immune activation in Gulf War veterans. Journal of Clinical Immunology, 24, 66–73.PubMedCrossRefGoogle Scholar
  53. Stanford, S. C. (2007). The open field test: Reinventing the wheel. J Psychopharmacol., 21, 134–135.PubMedCrossRefGoogle Scholar
  54. Steele, L. (2000). Prevalence and patterns of Gulf War illness in Kansas veterans: Association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology, 152, 992–1002.PubMedCrossRefGoogle Scholar
  55. Terry, A. V., Jr, Buccafusco, J. J., Gearhart, D. A., Beck, W. D., Middlemore-Risher, M. L., Truan, J. N., et al. (2011). Repeated, intermittent exposures to diisopropylfluorophosphate in rats: Protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function. Neuroscience, 176, 237–253.PubMedCrossRefGoogle Scholar
  56. Toomey, R., Alpern, R., Vasterling, J. J., Baker, D. G., Reda, D. J., Lyons, M. J., et al. (2009). Neuropsychological functioning of U.S. Gulf War veterans 10 years after the war. Journal of International Neuropsychology Society, 15, 717–729.CrossRefGoogle Scholar
  57. Vasterling, J. J., & Bremner, J. D. (2006). The impact of the 1991 Gulf War on the mind and brain: Findings from neuropsychological and neuroimaging research. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 361, 593–604.PubMedCrossRefGoogle Scholar
  58. Vythilingam, M., Luckenbaugh, D. A., Lam, T., Morgan, C. A., III, Lipschitz, D., Charney, D. S., et al. (2005). Smaller head of the hippocampus in Gulf War-related posttraumatic stress disorder. Psychiatry Research, 139, 89–99.PubMedCrossRefGoogle Scholar
  59. Wada-Isoe, K., Imamura, K., Kitamaya, M., Kowa, H., & Nakashima, K. (2008). Serum heart-fatty acid binding protein levels in patients with Lewy body disease. Journal of the Neurological Sciences, 266, 20–24.PubMedCrossRefGoogle Scholar
  60. Whistler, T., Fletcher, M. A., Lonergan, W., Zeng, X. R., Lin, J. M., Laperriere, A., et al. (2009). Impaired immune function in Gulf War Illness. BMC Medical Genomics 5, 2, 12.CrossRefGoogle Scholar
  61. White, R. F., Proctor, S. P., Heeren, T., Wolfe, J., Krengel, M., Vasterling, J., et al. (2001). Neuropsychological function in Gulf War veterans: relationships to self-reported toxicant exposures. American Journal of Industrial Medicine, 40, 42–54.PubMedCrossRefGoogle Scholar
  62. Zhang, Q., Zhou, X. D., Denny, T., Ottenweller, J. E., Lange, G., LaManca, J. J., et al. (1999). Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology, 6, 6–13.PubMedGoogle Scholar
  63. Zhang, W., Basile, A. S., Gomeza, J., Volpicelli, L. A., Levey, A. I., & Wess, J. (2002). Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. Journal of Neuroscience, 22, 1709–1717.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Laila Abdullah
    • 1
    • 2
  • Gogce Crynen
    • 1
    • 2
  • Jon Reed
    • 1
    • 3
  • Alex Bishop
    • 1
  • John Phillips
    • 1
  • Scott Ferguson
    • 1
    • 2
    • 3
  • Benoit Mouzon
    • 1
    • 2
    • 3
  • Myles Mullan
    • 1
    • 3
  • Venkatarajan Mathura
    • 1
  • Michael Mullan
    • 1
    • 3
  • Ghania Ait-Ghezala
    • 1
    • 2
    • 3
  • Fiona Crawford
    • 1
    • 2
    • 3
  1. 1.Roskamp InstituteSarasotaUSA
  2. 2.The Open UniversityWalton Hall, Milton KeynesUK
  3. 3.James A. Haley VA HospitalTampaUSA

Personalised recommendations