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Maternal Omega-3 Supplement Improves Dopaminergic System in Pre- and Postnatal Inflammation-Induced Neurotoxicity in Parkinson’s Disease Model

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Abstract

Evidence suggests that idiopathic Parkinson’s disease (PD) is the consequence of a neurodevelopmental disruption, rather than strictly a consequence of aging. Thus, we hypothesized that maternal supplement of omega-3 polyunsaturated fatty acids (ω-3 PUFA) may be associated with neuroprotection mechanisms in a self-sustaining cycle of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)-model of PD. To test this hypothesis, behavioral and neurochemical assay were performed in prenatally LPS-exposed offspring at postnatal day 21. To further determine whether prenatal LPS exposure and maternal ω-3 PUFAs supplementation had persisting effects, brain injury was induced on PN 90 rats, following bilateral intranigral LPS injection. Pre- and postnatal inflammation damage not only affected dopaminergic neurons directly, but it also modified critical features, such as activated microglia and astrocyte cells, disrupting the support provided by the microenvironment. Unexpectedly, our results failed to show any involvement of caspase-dependent and independent apoptosis pathway in neuronal death mechanisms. On the other hand, learning and memory deficits detected with a second toxic exposure were significantly attenuated in maternal ω-3 PUFAs supplementation group. In addition, ω-3 PUFAs promote beneficial effect on synaptic function, maintaining the neurochemical integrity in remaining neurons, without necessarily protect them from neuronal death. Thus, our results suggest that ω-3 PUFAs affect the functional ability of the central nervous system in a complex way in a multiple inflammation-induced neurotoxicity animal model of PD and they disclose new ways of understanding how these fatty acids control responses of the brain to different challenges.

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References

  1. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483

    Article  PubMed  Google Scholar 

  2. Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  CAS  PubMed  Google Scholar 

  4. Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, Ischiropoulos H (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci U S A 95:7659–7663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21:404–412

    Article  CAS  PubMed  Google Scholar 

  7. Barlow BK, Cory-Slechta DA, Richfield EK, Thiruchelvam M (2007) The gestational environment and Parkinson’s disease: evidence for neurodevelopmental origins of a neurodegenerative disorder. Reprod Toxicol 23:457–470

    Article  CAS  PubMed  Google Scholar 

  8. Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS, Carvey PM (2002) In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Mov Disord 17:116–124

    Article  PubMed  Google Scholar 

  9. Ling ZD, Chang Q, Lipton JW, Tong CW, Landers TM, Carvey PM (2004) Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain. Neuroscience 124:619–628

    Article  CAS  PubMed  Google Scholar 

  10. Ling Z, Chang QA, Tong CW, Leurgans SE, Lipton JW, Carvey PM (2004) Rotenone potentiates dopamine neuron loss in animals exposed to lipopolysaccharide prenatally. Exp Neurol 190:373–383

    Article  CAS  PubMed  Google Scholar 

  11. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W et al (2014) Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 112:24–49

    Article  CAS  PubMed  Google Scholar 

  12. Ulukaya E, Acilan C, Yilmaz Y (2011) Apoptosis: why and how does it occur in biology? Cell Biochem Funct 29:468–480

    Article  CAS  PubMed  Google Scholar 

  13. Yamada M, Kida K, Amutuhaire W, Ichinose F, Kaneki M (2010) Gene disruption of caspase-3 prevents MPTP-induced Parkinson’s disease in mice. Biochem Biophys Res Commun 402:312–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krantic S, Mechawar N, Reix S, Quirion R (2007) Apoptosis-inducing factor: a matter of neuron life and death. Prog Neurobiol 81:179–196

    Article  CAS  PubMed  Google Scholar 

  15. Cheung EC, Melanson-Drapeau L, Cregan SP, Vanderluit JL, Ferguson KL, McIntosh WC, Park DS, Bennett SA et al (2005) Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci 25:1324–1334

    Article  CAS  PubMed  Google Scholar 

  16. Wang H, Shimoji M, Yu SW, Dawson TM, Dawson VL (2003) Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson’s disease. Ann N Y Acad Sci 991:132–139

    Article  CAS  PubMed  Google Scholar 

  17. Stillwell W, Wassall SR (2003) Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids 126:1–27

    Article  CAS  PubMed  Google Scholar 

  18. Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH (2009) Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 284:27384–27392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Balogun KA, Cheema SK (2014) The expression of neurotrophins is differentially regulated by omega-3 polyunsaturated fatty acids at weaning and postweaning in C57BL/6 mice cerebral cortex. Neurochem Int 66:33–42

    Article  CAS  PubMed  Google Scholar 

  20. Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83:1505S–1519S

    CAS  PubMed  Google Scholar 

  21. Calder PC (2012) Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol 75:645–662

    Article  Google Scholar 

  22. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA (2003) Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 111:e39–44

    Article  PubMed  Google Scholar 

  23. Pudell C, Vicente BA, Delattre AM, Carabelli B, Mori MA, Suchecki D, Machado RB, Zanata SM et al (2014) Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats. Eur J Neurosci 39:266–274

    Article  PubMed  Google Scholar 

  24. Vines A, Delattre AM, Lima MM, Rodrigues LS, Suchecki D, Machado RB, Tufik S, Pereira SI et al (2012) The role of 5-HT(1)A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism. Neuropharmacology 62:184–191

    Article  CAS  PubMed  Google Scholar 

  25. McNamara RK, Carlson SE (2006) Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fat Acids 75:329–349

    Article  CAS  Google Scholar 

  26. Ling Z, Zhu Y, Tong C, Snyder JA, Lipton JW, Carvey PM (2006) Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally. Exp Neurol 199:499–512

    Article  CAS  PubMed  Google Scholar 

  27. Ferraz AC, Delattre AM, Almendra RG, Sonagli M, Borges C, Araujo P, Andersen ML, Tufik S et al (2011) Chronic omega-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol. Behav Brain Res 219:116–122

    Article  CAS  PubMed  Google Scholar 

  28. Goldman JM, Murr AS, Cooper RL (2007) The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res B Dev Reprod Toxicol 80:84–97

    Article  CAS  PubMed  Google Scholar 

  29. Lazic SE, Essioux L (2013) Improving basic and translational science by accounting for litter-to-litter variation in animal models. BMC Neurosci 14:37

    Article  PubMed  PubMed Central  Google Scholar 

  30. Paxinos G, Watson C (2005) The rat brain stereotaxic coordinates, vol 5. Academic, San Diego

    Google Scholar 

  31. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917

    Article  CAS  PubMed  Google Scholar 

  32. Joseph JD, Ackman RG (1992) Capillary column gas-chromatografic method for analysis of encapsulated fish oils and fish oil ethyl-esters—collaborative study. J AOAC Int 75:488–506

    CAS  Google Scholar 

  33. Broadhurst PL (1960) The place of animal psychology in the development of psychosomatic research. Fortschr Psychosom Med 1:63–69

    CAS  PubMed  Google Scholar 

  34. Machado RB, Tufik S, Suchecki D (2008) Chronic stress during paradoxical sleep deprivation increases paradoxical sleep rebound: association with prolactin plasma levels and brain serotonin content. Psychoneuroendocrinology 33:1211–1224

    Article  CAS  PubMed  Google Scholar 

  35. Lazzarini M, Martin S, Mitkovski M, Vozari RR, Stuhmer W, Bel ED (2013) Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model. Glia 61:1084–1100

    Article  PubMed  Google Scholar 

  36. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  37. Borsics T, Lundberg E, Geerts D, Koomoa DL, Koster J, Wester K, Bachmann AS (2010) Subcellular distribution and expression of prenylated Rab acceptor 1 domain family, member 2 (PRAF2) in malignant glioma: influence on cell survival and migration. Cancer Sci 101:1624–1631

    Article  CAS  PubMed  Google Scholar 

  38. Mittal P, Wing DA (2005) Urinary tract infections in pregnancy. Clin Perinatol 32:749–764

    Article  PubMed  Google Scholar 

  39. McDermott S, Callaghan W, Szwejbka L, Mann H, Daguise V (2000) Urinary tract infections during pregnancy and mental retardation and developmental delay. Obstet Gynecol 96:113–119

    CAS  PubMed  Google Scholar 

  40. Boksa P (2010) Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun 24:881–897

    Article  PubMed  Google Scholar 

  41. Arsenault D, St-Amour I, Cisbani G, Rousseau LS, Cicchetti F (2014) The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring. Brain Behav Immun 38:77–90

    Article  CAS  PubMed  Google Scholar 

  42. Girard S, Tremblay L, Lepage M, Sebire G (2010) IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol 184:3997–4005

    Article  CAS  PubMed  Google Scholar 

  43. Chao OY, Pum ME, Huston JP (2013) The interaction between the dopaminergic forebrain projections and the medial prefrontal cortex is critical for memory of objects: implications for Parkinson’s disease. Exp Neurol 247:373–382

    Article  PubMed  Google Scholar 

  44. Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF (2001) The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res 40:1–94

    Article  CAS  PubMed  Google Scholar 

  45. Green P, Glozman S, Kamensky B, Yavin E (1999) Developmental changes in rat brain membrane lipids and fatty acids. The preferential prenatal accumulation of docosahexaenoic acid. J Lipid Res 40:960–966

    CAS  PubMed  Google Scholar 

  46. Snyder-Keller A, Stark PF (2008) Prenatal inflammatory effects on nigrostriatal development in organotypic cultures. Brain Res 1233:160–167

    Article  CAS  PubMed  Google Scholar 

  47. Lin YL, Wang S (2014) Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats. Behav Brain Res 259:24–34

    Article  CAS  PubMed  Google Scholar 

  48. Baharnoori M, Brake WG, Srivastava LK (2009) Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats. Schizophr Res 107:99–109

    Article  PubMed  Google Scholar 

  49. Kumral A, Baskin H, Yesilirmak DC, Ergur BU, Aykan S, Genc S, Genc K, Yilmaz O et al (2007) Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neonatology 92:269–278

    Article  CAS  PubMed  Google Scholar 

  50. Cai Z, Pan ZL, Pang Y, Evans OB, Rhodes PG (2000) Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res 47:64–72

    Article  CAS  PubMed  Google Scholar 

  51. Roumier A, Pascual O, Bechade C, Wakselman S, Poncer JC, Real E, Triller A, Bessis A (2008) Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function. PLoS One 3, e2595

    Article  PubMed  PubMed Central  Google Scholar 

  52. Rousset CI, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E (2006) Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr Res 59:428–433

    Article  CAS  PubMed  Google Scholar 

  53. Bandeira F, Lent R, Herculano-Houzel S (2009) Changing numbers of neuronal and non-neuronal cells underlie postnatal brain growth in the rat. Proc Natl Acad Sci U S A 106:14108–14113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  56. Ling Z, Zhu Y, Tong CW, Snyder JA, Lipton JW, Carvey PM (2009) Prenatal lipopolysaccharide does not accelerate progressive dopamine neuron loss in the rat as a result of normal aging. Exp Neurol 216:312–320

    Article  CAS  PubMed  Google Scholar 

  57. Giordano G, Costa LG (2012) Developmental neurotoxicity: some old and new issues. ISRN Toxicol 2012:814795

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chen GH, Wang H, Yang QG, Tao F, Wang C, Xu DX (2011) Acceleration of age-related learning and memory decline in middle-aged CD-1 mice due to maternal exposure to lipopolysaccharide during late pregnancy. Behav Brain Res 218:267–279

    Article  CAS  PubMed  Google Scholar 

  59. De Jaeger X, Cammarota M, Prado MA, Izquierdo I, Prado VF, Pereira GS (2013) Decreased acetylcholine release delays the consolidation of object recognition memory. Behav Brain Res 238:62–68

    Article  PubMed  Google Scholar 

  60. Nagy PM, Aubert I (2015) Overexpression of the vesicular acetylcholine transporter enhances dendritic complexity of adult-born hippocampal neurons and improves acquisition of spatial memory during aging. Neurobiol Aging 36:1881–1889

    Article  CAS  PubMed  Google Scholar 

  61. Das UN (2013) Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 42:122–134

    Article  CAS  PubMed  Google Scholar 

  62. Zugno AI, Chipindo H, Canever L, Budni J, Alves de Castro A, Bittencourt de Oliveira M, Heylmann AS, Gomes Wessler P et al (2015) Omega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia. Life Sci 121:65–69

    Article  CAS  PubMed  Google Scholar 

  63. Su HM (2010) Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem 21:364–373

    Article  CAS  PubMed  Google Scholar 

  64. Kitajka K, Puskas LG, Zvara A, Hackler L Jr, Barcelo-Coblijn G, Yeo YK, Farkas T (2002) The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci U S A 99:2619–2624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lesa GM, Palfreyman M, Hall DH, Clandinin MT, Rudolph C, Jorgensen EM, Schiavo G (2003) Long chain polyunsaturated fatty acids are required for efficient neurotransmission in C. elegans. J Cell Sci 116:4965–4975

    Article  CAS  PubMed  Google Scholar 

  66. Feng Y, Jankovic J, Wu YC (2015) Epigenetic mechanisms in Parkinson’s disease. J Neurol Sci 349:3–9

    Article  CAS  PubMed  Google Scholar 

  67. Burguillos MA, Hajji N, Englund E, Persson A, Cenci AM, Machado A, Cano J, Joseph B et al (2011) Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson’s disease patients. Neurobiol Dis 41:177–188

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors are indebted to Laboratório Herbarium Botânico S/A, which kindly donated the fish oil capsules rich in DHA and EPA. ACF is the recipient of Fundação Araucária - Governo do Estado do Paraná fellowship. DS, SMZ, and MMSL are recipients of CNPq fellowship.

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Correspondence to Ana Marcia Delattre or Anete C. Ferraz.

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Delattre, A.M., Carabelli, B., Mori, M.A. et al. Maternal Omega-3 Supplement Improves Dopaminergic System in Pre- and Postnatal Inflammation-Induced Neurotoxicity in Parkinson’s Disease Model. Mol Neurobiol 54, 2090–2106 (2017). https://doi.org/10.1007/s12035-016-9803-8

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