Neurotoxicity Research

, Volume 35, Issue 4, pp 918–930 | Cite as

Local Gastrointestinal Injury Exacerbates Inflammation and Dopaminergic Cell Death in Parkinsonian Mice

  • Ana-Luisa Gil-Martínez
  • Cristina Estrada
  • Lorena Cuenca
  • Juan-Antonio Cano
  • Manuel Valiente
  • Carlos-Manuel Martínez-Cáceres
  • Emiliano Fernández-Villalba
  • María-Trinidad HerreroEmail author
Original Article


The cause of progressive degeneration in Parkinson’s disease is not clear, although, in the last years, different studies have suggested that both brain and peripheral inflammation could play a key role in the progression of this disorder. In our study, we aimed to analyze the effect of an acute inflammation confined to the colon on dopaminergic neuronal death and glial response in mice intoxicated with MPTP. The results obtained show a very significant decrease of dopaminergic neurons in the SNpc as well as a significant decrease of dopaminergic fibers in the striatum of the MPTP+DSS-treated group compared with the control animals. In addition, there was a significant exacerbation of microglial and astrocytes activation in MPTP+DSS animals compared with the control group. This data suggests that a specific gastrointestinal injury, which induces a systemic inflammatory response, is able to exacerbate cell death mechanisms of the remaining dopaminergic neurons and then contributes to the persistent progression of the disease. These results leave open new lines of research on the role of exclusive colonic inflammation and the progression of nigrostriatal dopaminergic degeneration.


Parkinson’s disease Ulcerative colitis Systemic inflammation Neurodegeneration 





Disease activity index


Dextran sodium sulfate


Glial fibrillary acidic protein




Leucine-rich repeat kinase 2




Nitric oxide


Reactive oxygen species


Substantia nigra pars compacta


Tyrosine hydroxylase



Research work of the authors was supported by the Spanish Ministry of Science and Innovation (FIS PI13 01293), Fundación Séneca (19540/PI/14) and “Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development” (European Community’s Seventh Framework Programme (FP7/2007-2013) for the Innovative Medicine Initiative under Grant Agreement No 115009) to MTH.

Author Contributions

MTH designed the research; ALGM and CE performed the research and analyzed the data; JAC, MV, CMMC, and EFV contributed to the care of the animals and histological quantifications; LC discussed the in vivo results; ALGM and MTH discussed all the results and wrote the paper.

Compliance with Ethical Standards

All procedures related to animal maintenance, care and experimentation were carried out in accordance with the European Community Council Directive (2010/63/UE) for animals to be used in preclinical studies and were approved by the Institutional Committee on Animal Ethics of the University of Murcia (REGA ES300305440012).

Conflicts of Interest

The authors declare that they have no conflicts of interest.


  1. Annese V, Herrero MT, Di Pentima M, Gomez A, Lombardi L, Ros CM et al (2015) Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Brain Struct Funct 220:703–727CrossRefGoogle Scholar
  2. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 13:221–227CrossRefGoogle Scholar
  3. Barcia C, De Pablos V, Bautista-Hernández V, Sánchez-Bahillo Á, Bernal I, Fernández-Villalba E et al (2005) Increased plasma levels of TNF-α but not of IL1-β in MPTP-treated monkeys one year after the MPTP administration. Park Relat Disord 11:435–439CrossRefGoogle Scholar
  4. Barcia C, Ros CM, Annese V, Gómez A, Ros-Bernal F, Aguado-Yera D et al (2011) IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 2:e142CrossRefGoogle Scholar
  5. Barcia C, Ros CM, Annese V, Carrillo-de Sauvage MA, Ros-Bernal F, Gómez A, Yuste JE, Campuzano CM, de Pablos V, Fernandez-Villalba E, Herrero MT (2012) ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo. Sci Rep 2:809CrossRefGoogle Scholar
  6. Blesa J, Pifl C, Sánchez-González MA, Juri C, García-Cabezas MA, Adánez R, Iglesias E, Collantes M, Peñuelas I, Sánchez-Hernández JJ, Rodríguez-Oroz MC, Avendaño C, Hornykiewicz O, Cavada C, Obeso JA (2012) The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study. Neurobiol Dis 48:79–91CrossRefGoogle Scholar
  7. Braak H, Del K, Rüb U, De Vos RAI, Jansen ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefGoogle Scholar
  8. Braak H, De Vos RAI, Bohl J, Del Tredici K (2006) Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72CrossRefGoogle Scholar
  9. Carrillo-de Sauvage MÁ, Maatouk L, Arnoux I, Pasco M, Sanz Diez A, Delahaye M et al (2013) Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation. Cell Death Differ 20:1546–1557CrossRefGoogle Scholar
  10. Chassaing B, Srinivasan G, Delgado MA, Young AN, Gewirtz AT, Vijay-Kumar M (2012) Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation. PLoS One 7:e44328CrossRefGoogle Scholar
  11. Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M (2014) Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol 104:Unit 15.25Google Scholar
  12. Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F et al (2015) Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol Commun 3:12CrossRefGoogle Scholar
  13. Collins LM, Toulouse A, Connor TJ, Nolan YM (2012) Contributions of central and systemic inflammation to the pathophysiology of Parkinson’s disease. Neuropharmacology 62:2153–2167CrossRefGoogle Scholar
  14. Côté M, Poirier AA, Aubé B, Jobin C, Lacroix S, Soulet D (2015) Partial depletion of the proinflammatory monocyte population is neuroprotective in the myenteric plexus but not in the basal ganglia in a MPTP mouse model of Parkinson’s disease. Brain Behav Immun 46:154–167CrossRefGoogle Scholar
  15. De Lella Ezcurra AL, Chertoff M, Ferrari C, Graciarena M, Pitossi F (2010) Chronic expression of low levels of tumor necrosis factor-α in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiol Dis 37:630–640CrossRefGoogle Scholar
  16. Dzamko N, Rowe DB, Halliday GM (2016) Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers. Mov Disord 31:889–897CrossRefGoogle Scholar
  17. Engelender S, Isacson O (2016) The threshold theory for Parkinson’s disease. Trends Neurosci 40:4–14CrossRefGoogle Scholar
  18. Garrido-Gil P, Rodriguez-Perez AI, Dominguez-Meijide A, Guerra MJ, Labandeira-Garcia JL (2018) Bidirectional neural interaction between central dopaminergic and gut lesions in Parkinson’s disease models. Mol Neurobiol 55:7297–7316CrossRefGoogle Scholar
  19. Glass CK, Saijo K, Winner B, Marchetto MC, Gage H (2010) Mechanisms Underlying Inflammation in neurodegeneration. Glass 140:918–934Google Scholar
  20. Godoy MCP, Tarelli R, Ferrari CC, Sarchi MI, Pitossi FJ (2008) Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease. Brain 131:1880–1894CrossRefGoogle Scholar
  21. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26:6–17CrossRefGoogle Scholar
  22. Han Y, Zhao T, Cheng X, Zhao M, Gong S-H, Zhao Y-Q, … Zhu L-L (2018) Cortical inflammation is increased in a DSS-induced colitis mouse model. Neurosci. BullGoogle Scholar
  23. Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K et al (2015) Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease Satoru. PLoS One 10:1–15Google Scholar
  24. Hilel AS, Gysemans B, A, M.E.M.L., Heymanns ANAC (2018) Dextran sulphate of sodium-induced colitis in mice: antihyperalgesic effects of ethanolic extract of Citrus reticulata and potential damage to the central nervous system. Ann Brazilian Acad Sci 90:3139–3145CrossRefGoogle Scholar
  25. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, Wang ZY, Roybon L, Melki R, Li JY (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820CrossRefGoogle Scholar
  26. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386:896–912CrossRefGoogle Scholar
  27. Laroui H, Ingersoll SA, Liu HC, Baker MT, Ayyadurai S, Charania MA, Laroui F, Yan Y, Sitaraman SV, Merlin D (2012) Dextran sodium sulfate (DSS) induces colitis in mice by forming nano-lipocomplexes with medium-chain-length fatty acids in the colon. PLoS One 7:e32084CrossRefGoogle Scholar
  28. Larrosa M, González-Sarrías A, Yáñez-Gascón MJ, Selma MV, Azorín-Ortuño M, Toti S, Tomás-Barberán F, Dolara P, Espín JC (2010) Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem 21:717–725CrossRefGoogle Scholar
  29. Lee H-J, Suk J-E, Patrick C, Bae E-J, Cho J-H, Rho S, Hwang D, Masliah E, Lee SJ (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272CrossRefGoogle Scholar
  30. Lim CK, Fernandez-Gomez FJ, Braidy N, Estrada C, Costa C, Costa S, … Guillemin GJ (2016) Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Prog NeurobiolGoogle Scholar
  31. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483CrossRefGoogle Scholar
  32. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291CrossRefGoogle Scholar
  33. Melo-Thomas L, Gil-Martínez AL, Cuenca L, Estrada C, Gonzalez-Cuello A, Schwarting RK, Herrero MT (2018) Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice. Neurotoxicology 65:38–43CrossRefGoogle Scholar
  34. Ogura T, Ogata M, Akita H, Jitsuki S, Akiba L, Noda K, Hoka S, Saji M (2005) Impaired acquisition of skilled behavior in rotarod task by moderate depletion of striatal dopamine in a pre-symptomatic stage model of Parkinson’s disease. Neurosci Res 51:299–308CrossRefGoogle Scholar
  35. Paxinos G, Franklin K (2012 ) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates, 4th edn. Academic PressGoogle Scholar
  36. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167CrossRefGoogle Scholar
  37. Perše M, Cerar A (2012) Dextran sodium sulphate colitis mouse model: traps and tricks. J Biomed Biotechnol 2012:1–13Google Scholar
  38. Pfeiffer RF (2016) Non-motor symptoms in Parkinson’s disease. Park Relat Disord 22:S119–S122CrossRefGoogle Scholar
  39. Qian L, Flood PM, Hong JS (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117:971–979CrossRefGoogle Scholar
  40. Qin L, Wu X, Block ML, Liu Y, Breese GR, Knapp DJ et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462CrossRefGoogle Scholar
  41. Rozas G, Guerra MJ, Labandeira-García JL (1997) An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Res Protocol 2:75–84CrossRefGoogle Scholar
  42. 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 137:47–59CrossRefGoogle Scholar
  43. Stefano MED, Herrero MT (2016) The multifaceted role of metalloproteinases in physiological and pathological conditions in embryonic and adult brains. Prog NeurobiolGoogle Scholar
  44. Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Natl Inst Heal 37:510–518Google Scholar
  45. Titova N, Qamar MA, Chaudhuri KR (2017) The nonmotor features of Parkinson’s disease. Elsevier Inc., AmsterdamGoogle Scholar
  46. Tysnes OB, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm 124:901–905CrossRefGoogle Scholar
  47. Villaran RF, Espinosa-Oliva AM, Sarmiento M, De Pablos RM, Arguelles S, Delgado-Cortes MJ et al (2010) Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson’s disease. J Neurochem 114:1687–1700CrossRefGoogle Scholar
  48. Wang Q, Liu Y, Zhou J (2015a) Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener 4:19CrossRefGoogle Scholar
  49. Wang S, Jing H, Yang H, Liu Z, Guo H, Chai L, Hu L (2015b) Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. J Ethnopharmacol 164:247–255CrossRefGoogle Scholar
  50. Zhou X, Spittau B, Krieglstein K (2012) TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation 9:210CrossRefGoogle Scholar
  51. Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS et al (2015) Chronic intestinal inflammation alters hippocampal neurogenesis. J Neuroinflammation 12:1–12CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ana-Luisa Gil-Martínez
    • 1
    • 2
  • Cristina Estrada
    • 1
    • 2
  • Lorena Cuenca
    • 1
    • 2
  • Juan-Antonio Cano
    • 1
  • Manuel Valiente
    • 1
  • Carlos-Manuel Martínez-Cáceres
    • 3
  • Emiliano Fernández-Villalba
    • 1
    • 2
  • María-Trinidad Herrero
    • 1
    • 2
    Email author
  1. 1.Clinical and Experimental Neuroscience Group (NiCE-IMIB), Department of Human Anatomy and Psychobiology, Institute for Aging Research, School of MedicineUniversity of MurciaMurciaSpain
  2. 2.Biomedical Research Institute of Murcia (IMIB-Arrixaca), Campus of Health SciencesUniversity of MurciaMurciaSpain
  3. 3.Biomedical Research Institute of Murcia, University Hospital “Virgen de la Arrixaca”, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasUniversity of MurciaMurciaSpain

Personalised recommendations