Immunologic Research

, Volume 65, Issue 1, pp 99–105

Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior in mice

  • Shaye Kivity
  • Maria-Teresa Arango
  • Nicolás Molano-González
  • Miri Blank
  • Yehuda Shoenfeld
Environment and Autoimmunity

Abstract

Human papillomavirus vaccine (HPVv) is used worldwide for prevention of infection. However several reports link this vaccine, with immune-mediated reactions, especially with neurological manifestations. Our previous results showed that HPVv-Gardasil and aluminum-immunized mice developed behavioral impairments. Studies have shown a positive effect of phospholipid supplementation on depression and cognitive functions in mice. Therefore, our goal was to evaluate the effect of a dietary supplement on vaccine-induced depression. Sixty C57BL/6 female mice were immunized with HPVv-Gardasil, aluminum or the vehicle (n = 20 each group), and half of each group were fed 5 times per week with 0.2 ml of a dietary supplement enriched with phosphatidylcholine. The mice were evaluated for depression at 3 months of age, by the forced swimming test. Both the Gardasil and the aluminum-treated mice developed depressive-like behavior when compared to the control group. The HPVv-Gardasil-immunized mice supplemented with phosphatidylcholine significantly reduced their depressive symptoms. This study confirms our previous studies demonstrating depressive-like behavior in mice vaccinated with HPVv-Gardasil. In addition, it demonstrates the ability of phosphatidylcholine-enriched diet to attenuate depressive-like behavior in the HPVv-Gardasil-vaccinated mice. We suggest that phosphatidylcholine supplementation may serve as a treatment for patients suffering vaccine-related neurological manifestations.

Keywords

Gardasil Aluminum Depression Behavior Autoimmunity 

Abbreviations

HPVv

Human papillomavirus vaccine

HPV

Human papillomavirus

ASIA

Autoimmune/inflammatory syndrome induced by adjuvants

PC

Phosphatidylcholine

FST

Forced swimming test

MANOVA

Multivariate analysis of variance

CNS

Central nervous system

CFS

Chronic fatigue syndrome

PS

Phosphatidylserine

GC

Glucocorticoid

References

  1. 1.
    Kash N, et al. Safety and Efficacy data on vaccines and immunization to human papillomavirus. J Clin Med. 2015;4(4):614–33. doi:10.3390/jcm4040614.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    McCormack PL, Joura EA. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil(R)): a review of its use in the prevention of premalignant genital lesions, genital cancer and genital warts in women. Drugs. 2010;70(18):2449–74. doi:10.2165/11204920-000000000-00000.PubMedCrossRefGoogle Scholar
  3. 3.
    McCormack PL. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (gardasil((R))): a review of its use in the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts. Drugs. 2014;74(11):1253–83. doi:10.1007/s40265-014-0255-z.PubMedCrossRefGoogle Scholar
  4. 4.
    Gatto M, et al. Human papillomavirus vaccine and systemic lupus erythematosus. Clin Rheumatol. 2013;32(9):1301–7. doi:10.1007/s10067-013-2266-7.PubMedCrossRefGoogle Scholar
  5. 5.
    Geier DA, Geier MR. A case-control study of quadrivalent human papillomavirus vaccine-associated autoimmune adverse events. Clin Rheumatol. 2015;34(7):1225–31. doi:10.1007/s10067-014-2846-1.PubMedCrossRefGoogle Scholar
  6. 6.
    Inbar R, et al. Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol Res. 2016. doi:10.1007/s12026-016-8826-6.PubMedGoogle Scholar
  7. 7.
    Pellegrino P, et al. On the relationship between human papilloma virus vaccine and autoimmune diseases. Autoimmun Rev. 2014;13(7):736–41. doi:10.1016/j.autrev.2014.01.054.PubMedCrossRefGoogle Scholar
  8. 8.
    Tomljenovic L, Shaw CA. Human papillomavirus (HPV) vaccine policy and evidence-based medicine: are they at odds? Ann Med. 2013;45(2):182–93. doi:10.3109/07853890.2011.645353.PubMedCrossRefGoogle Scholar
  9. 9.
    Kanduc D. Potential cross-reactivity between HPV16 L1 protein and sudden death-associated antigens. J Exp Ther Oncol. 2011;9(2):159–65.PubMedGoogle Scholar
  10. 10.
    Kanduc D. Quantifying the possible cross-reactivity risk of an HPV16 vaccine. J Exp Ther Oncol. 2009;8(1):65–76.PubMedGoogle Scholar
  11. 11.
    Li Z, Vance DE. Phosphatidylcholine and choline homeostasis. J Lipid Res. 2008;49(6):1187–94. doi:10.1194/jlr.R700019-JLR200.PubMedCrossRefGoogle Scholar
  12. 12.
    Tayebati SK, Amenta F. Choline-containing phospholipids: relevance to brain functional pathways. Clin Chem Lab Med. 2013;51(3):513–21. doi:10.1515/cclm-2012-0559.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim HY, et al. Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res. 2014;56:1–18. doi:10.1016/j.plipres.2014.06.002.PubMedCrossRefGoogle Scholar
  14. 14.
    Vickers MH, et al. Supplementation with a mixture of complex lipids derived from milk to growing rats results in improvements in parameters related to growth and cognition. Nutr Res. 2009;29(6):426–35. doi:10.1016/j.nutres.2009.06.001.PubMedCrossRefGoogle Scholar
  15. 15.
    Rondanelli M, et al. Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly depression: effects on depressive symptoms, on phospholipids fatty acids profile and on health-related quality of life. J Nutr Health Aging. 2011;15(1):37–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Rondanelli M, et al. Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: a double-blind, placebo-controlled, randomized clinical trial. J Am Coll Nutr. 2010;29(1):55–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Benton D, et al. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci. 2001;4(3):169–78.PubMedCrossRefGoogle Scholar
  18. 18.
    Katzav A, et al. Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system. Arthritis Rheum. 2007;56(3):938–48. doi:10.1002/art.22419.PubMedCrossRefGoogle Scholar
  19. 19.
    Porsolt RD, et al. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1997;229:327–36.Google Scholar
  20. 20.
    Katzav A, et al. Anti-P ribosomal antibodies induce defect in smell capability in a model of CNS -SLE (depression). J Autoimmun. 2008;31(4):393–8. doi:10.1016/j.jaut.2008.09.002.PubMedCrossRefGoogle Scholar
  21. 21.
    De Rosario-Martinez H, et al. Post-Hoc interaction Analysis—package ‘phia’. 0.2-1 ed2015. 2015. https://cran.r-project.org/web/packages/phia/phia.pdf
  22. 22.
    Alijotas-Reig J. Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria. Lupus. 2015;24(10):1012–8. doi:10.1177/0961203315579092.PubMedCrossRefGoogle Scholar
  23. 23.
    Karussis D, Petrou P. The spectrum of post-vaccination inflammatory CNS demyelinating syndromes. Autoimmun Rev. 2013;13(3):215–24. doi:10.1016/j.autrev.2013.10.003.CrossRefGoogle Scholar
  24. 24.
    Narcolepsy AS, et al. A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants. J Autoimmun. 2009;50:1–11. doi:10.1016/j.jaut.2014.01.033.Google Scholar
  25. 25.
    McCarthy JE, Filiano J. Opsoclonus Myoclonus after human papilloma virus vaccine in a pediatric patient. Parkinsonism Relat Disord. 2009;15(10):792–4. doi:10.1016/j.parkreldis.2009.04.002.PubMedCrossRefGoogle Scholar
  26. 26.
    Colafrancesco S, et al. HPV vaccines and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Am J Reprod Immunol. 2013;70(4):309–16.PubMedCrossRefGoogle Scholar
  27. 27.
    Shaw CA, Petrik MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem. 2009;103(11):1555–62. doi:10.1016/j.jinorgbio.2009.05.019.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Rogers MA, Simon DG. A preliminary study of dietary aluminium intake and risk of Alzheimer’s disease. Age Aging. 1999;28(2):205–9.CrossRefGoogle Scholar
  29. 29.
    Bishop NJ, et al. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N Engl J Med. 1997;336(22):1557–61. doi:10.1056/NEJM199705293362203.PubMedCrossRefGoogle Scholar
  30. 30.
    Walton JR. Evidence that ingested aluminum additives contained in processed foods and alum-treated drinking water are a major risk factor for Alzheimer’s disease. Curr Inorg Chem. 2012;2(1):19–39.CrossRefGoogle Scholar
  31. 31.
    Rondeau V, et al. Relation between aluminum concentrations in drinking water and Alzheimer’s disease: an 8-year follow-up study. Am J Epidemiol. 2000;152(1):59–66.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    ATSDR. Toxicological profile for aluminum. Atlanta: Agency for toxic substances and disease registry; 2008.Google Scholar
  33. 33.
    Tomljenovic L. Aluminum and Alzheimer’s disease: after a century of controversy, is there a plausible link? J Alzheimers Dis. 2011;23(4):567–98. doi:10.3233/Jad-2010-101494.PubMedGoogle Scholar
  34. 34.
    Perl DP, Moalem S. Aluminum, Alzheimer’s disease and the geospatial occurrence of similar disorders. Rev Mineral Geochem. 2006;64:115–34.CrossRefGoogle Scholar
  35. 35.
    Authier FJ, et al. Central nervous system disease in patients with macrophagic myofasciitis. Brain. 2001;124(Pt 5):974–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Exley C, et al. Elevated urinary excretion of aluminium and iron in multiple sclerosis. Mult Scler. 2006;12(5):533–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Melendez L, et al. Aluminium and other metals may pose a risk to children with autism spectrum disorder: biochemical and behavioural impairments. Clin Exp Pharmacol. 2013;3(1):120. doi:10.4172/2161-1459.1000120.CrossRefGoogle Scholar
  38. 38.
    Tomljenovic L, Shaw CA. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J Inorg Biochem. 2011;105(11):1489–99. doi:10.1016/j.jinorgbio.2011.08.008.PubMedCrossRefGoogle Scholar
  39. 39.
    Seneff S, et al. Empirical data confirm autism symptoms related to aluminum and acetaminophen exposure. Entropy. 2012;14:2227–53.CrossRefGoogle Scholar
  40. 40.
    Redhead K, et al. Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Pharmacol Toxicol. 1992;70(4):278–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Khan Z, et al. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMC Med. 2013;11:99. doi:10.1186/1741-7015-11-99.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lujan L, et al. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol Res. 2013;56(2–3):317–24. doi:10.1007/s12026-013-8404-0.PubMedCrossRefGoogle Scholar
  43. 43.
    Vasudevaraju P, et al. Molecular toxicity of aluminium in relation to neurodegeneration. Indian J Med Res. 2008;128(4):545–56.PubMedGoogle Scholar
  44. 44.
    Obulesu M, Rao DM. Animal models of Alzheimer’s disease: an understanding of pathology and therapeutic avenues. Int J Neurosci. 2010;120(8):531–7. doi:10.3109/00207451003760080.PubMedCrossRefGoogle Scholar
  45. 45.
    Kumar V, et al. Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminium. Brain Res. 2008;1232:94–103. doi:10.1016/j.brainres.2008.07.028.PubMedCrossRefGoogle Scholar
  46. 46.
    Agarwal SK, et al. Evaluation of the developmental neuroendocrine and reproductive toxicology of aluminium. Food Chem Toxicol. 1996;34(1):49–53. doi:10.1016/0278-6915(95)00088-7.PubMedCrossRefGoogle Scholar
  47. 47.
    Singla N, Dhawan DK. Regulatory role of zinc during aluminium-induced altered carbohydrate metabolism in rat brain. J Neurosci Res. 2012;90(3):698–705. doi:10.1002/jnr.22790.PubMedCrossRefGoogle Scholar
  48. 48.
    Walton JR. Aluminum Disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer’s disease. J Alzheimers Dis. 2012;29(2):255–73. doi:10.3233/JAD-2011-111712.PubMedGoogle Scholar
  49. 49.
    Shafer TJ, et al. Mechanisms underlying AlCl3 inhibition of agonist-stimulated inositol phosphate accumulation. Role of calcium, G-proteins, phospholipase C and protein kinase C. Biochem Pharmacol. 1994;47(8):1417–25. doi:10.1016/0006-2952(94)90342-5.PubMedCrossRefGoogle Scholar
  50. 50.
    Agmon-Levin N, et al. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model. J Autoimmun. 2014;54:21–32. doi:10.1016/j.jaut.2014.06.006.PubMedCrossRefGoogle Scholar
  51. 51.
    Kullenberg D, et al. Health effects of dietary phospholipids. Lipids Health Dis. 2012;11:3. doi:10.1186/1476-511X-11-3.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Yechiel E, Barenholz Y. Relationships between membrane lipid composition and biological properties of rat myocytes. Effects of aging and manipulation of lipid composition. J Biol Chem. 1985;260(16):9123–31.PubMedGoogle Scholar
  53. 53.
    Nicolson GL, Ash ME. Lipid replacement therapy: a natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function. Biochim Biophys Acta. 1838;6:1657–79. doi:10.1016/j.bbamem.2013.11.010.Google Scholar
  54. 54.
    Borella E, et al. Lipid replacement therapy: is it a new approach in patients with chronic fatigue syndrome? J Autoimmune Dis Rheumatol. 2014;2:28–34.CrossRefGoogle Scholar
  55. 55.
    Corwin J, et al. Behavioral effects of phosphatidylserine in the aged Fischer 344 rat: amelioration of passive avoidance deficits without changes in psychomotor task performance. Neurobiol Aging. 1985;6(1):11–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Park HJ, et al. Enhanced learning and memory of normal young rats by repeated oral administration of Krill Phosphatidylserine. Nutr Neurosci. 2013;16(2):47–53. doi:10.1179/1476830512Y.0000000029.PubMedCrossRefGoogle Scholar
  57. 57.
    Kanno T, et al. DL-/PO-phosphatidylcholine restores restraint stress-induced depression-related behaviors and spatial memory impairment. Behav Pharmacol. 2014;25(5–6):575–81. doi:10.1097/FBP.0000000000000063.PubMedGoogle Scholar
  58. 58.
    Baumeister J, et al. Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress. Nutr Neurosci. 2008;11(3):103–10. doi:10.1179/147683008X301478.PubMedCrossRefGoogle Scholar
  59. 59.
    Vakhapova V, et al. Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: a double-blind placebo-controlled trial. Dement Geriatr Cogn Disord. 2010;29(5):467–74. doi:10.1159/000310330.PubMedCrossRefGoogle Scholar
  60. 60.
    Kato-Kataoka A, et al. Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints. J Clin Biochem Nutr. 2010;47(3):246–55. doi:10.3164/jcbn.10-62.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Manuel Y Keenoy B, et al. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci. 2001;68(17):2037–49.PubMedCrossRefGoogle Scholar
  62. 62.
    Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. 2000;54(1):115–25. doi:10.1054/mehy.1998.0825.PubMedCrossRefGoogle Scholar
  63. 63.
    Richards RS, et al. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep. 2000;5(1):35–41. doi:10.1179/rer.2000.5.1.35.PubMedCrossRefGoogle Scholar
  64. 64.
    Tayebati SK, Amenta F. Choline-containing phospholipids: relevance to brain functional pathways. Clin Chem Lab Med. 2013;51(3):513–21. doi:10.1515/cclm-2012-0559.PubMedCrossRefGoogle Scholar
  65. 65.
    Delwaide PJ, et al. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand. 1986;73(2):136–40.PubMedCrossRefGoogle Scholar
  66. 66.
    Glade MJ, Smith K. Phosphatidylserine and the human brain. Nutrition. 2015;31(6):781–6. doi:10.1016/j.nut.2014.10.014.PubMedCrossRefGoogle Scholar
  67. 67.
    Oliveira TG, et al. The impact of chronic stress on the rat brain lipidome. Mol Psychiatry. 2016;21(1):80–8. doi:10.1038/mp.2015.14.PubMedCrossRefGoogle Scholar
  68. 68.
    Leon A, et al. Effect of brain cortex phospholipids on adenylate-cyclase activity of mouse brain. J Neurochem. 1978;30(1):23–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Casamenti F, et al. Effect of phosphatidylserine on acetylcholine output from the cerebral cortex of the rat. J Neurochem. 1979;32(2):529–33.PubMedCrossRefGoogle Scholar
  70. 70.
    Casamenti F, et al. Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: a microdialysis study. Eur J Pharmacol. 1991;194(1):11–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Ali HA, et al. Quercetin and omega 3 ameliorate oxidative stress induced by aluminium chloride in the brain. J Mol Neurosci. 2014;53(4):654–60. doi:10.1007/s12031-014-0232-8.PubMedCrossRefGoogle Scholar
  72. 72.
    Nicolson GL, Conklin KA. Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis. 2008;25(2):161–9. doi:10.1007/s10585-007-9129-z.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Shaye Kivity
    • 1
    • 2
    • 3
    • 4
  • Maria-Teresa Arango
    • 1
    • 2
    • 5
  • Nicolás Molano-González
    • 6
  • Miri Blank
    • 1
    • 2
  • Yehuda Shoenfeld
    • 1
    • 2
    • 7
  1. 1.Zabludowicz Center for Autoimmune DiseasesSheba Medical CenterTel-HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Rheumatic Disease UnitSheba Medical CenterTel-HashomerIsrael
  4. 4.The Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2013Sheba Medical CenterTel-HashomerIsrael
  5. 5.Doctoral Program in Biomedical SciencesUniversidad del RosarioBogotáColombia
  6. 6.Center for Autoimmune Diseases Research (CREA)-Statistics, School of Medicine and Health SciencesUniversidad del RosarioBogotáColombia
  7. 7.Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune DiseasesTel Aviv UniversityTel AvivIsrael

Personalised recommendations