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Parkinson's disease and inflammatory changes

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Abstract

In 1988 McGeer and colleagues (Neurology 38, 1285–91) observed an activation of the microglia in substantia nigrapars compacta (SNpc) and striatum of brains from patients with Parkinson's disease. In the years that followed several studies performed in the cerebrospinal fluid and duringpost-mortem analysis in parkinsonian patients revealed increased levels of cytokines, suggesting the activation of a proinflammatory response. Moreover, Langston and his group described the presence of active microglia in the SNpc of three patients who had been exposed to MPTP several years before death. These results suggested that the inflammatory response may increase negative feed-back into the damaged area of the cerebral parenchyma, inducing an imbalance that could perpetuate and/or accelerate neuronal death over a period of years. Similar results have been obtained in parkinsonian monkeys, rats and mice. For these reasons, several groups have treated parkinsonian animals with different anti-inflammatory drugs and obtained promising results. However, it is still not known whether inflammatory changes are responsible for active nerve cell death or whether they play a protective role in neurodegeneration. These changes are putatively related to neuronal loss and suggest that anti-inflammatory treatment for parkinsonian patients could have beneficial effects in the progression of the disease by slowing down the process of neuronal loss.

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References

  • Akassoglou K, L Probert, G Kontogeorgos and G Kollias (1997) Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice.J. Immunol. 158, 438–445.

    PubMed  CAS  Google Scholar 

  • Alon T, I Hemo, A Itin, J Pe'er, J Stone and E Keshet (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.Nat. Med. 1, 1024–1028.

    Article  PubMed  CAS  Google Scholar 

  • Barcia C, E Fernández-Villalba, JM Navarro-Ruiz, V Garcia, JL Saez-Cassanelli and MT Herrero (2002a) Active cytokines in chronic parkinsonian monkeys one year after last MPTP exposure. Clinical and post-mortem study.Soc. Neurosci. Prgm. No. 485.16. [Abstract]

  • Barcia C, A Sánchez-Bahillo, V Bautista-Hernández, JM Navarro-Ruiz, E Fernández-Villalba, B Faucheux, EC Hirsch and MT Herrero (2002b) Blood vessels and neurodegeneration in Parkinson's disease. Study in chronic MPTP-treated monkeys, In: Nicholson and Faull (Eds.),The Basal Ganglia VII (Kluwer Academic/Plenum Publishers, New York), pp 341–347.

    Google Scholar 

  • Bauer J, F Berkenbosch, AM Van Dam and CD Dijkstra (1993) Demonstration of interleukin-1 beta in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultrastructural level.J. Neuroimmunol. 48, 13–21.

    Article  PubMed  CAS  Google Scholar 

  • Benjamin LE, I Hemo and E Keshet (1998) A plasticity window for blood vessel remodeling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF.Development 125, 1591–1598.

    PubMed  CAS  Google Scholar 

  • Benveniste EN (1995)Human Cytokines: Their Role in Research and Therapy, In: Aggarawal B and Puri R. (Eds.), (Blackwell Scientific Publications, Oxford, UK), pp 195–216.

    Google Scholar 

  • Blum-Degen D, T Muller, W Kuhn, M Gerlach, H Przuntek and P Riederer (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients.Neurosci. Lett. 202, 17–20.

    Article  PubMed  CAS  Google Scholar 

  • Boka G, P Anglade, D Wallach, F Javoy-Agid, Y Agid and EC Hirsch (1994) Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease.Neurosci. Lett. 172, 151–154.

    Article  PubMed  CAS  Google Scholar 

  • Campbell IL (2001) Cytokine-mediated inflammation and signalling in the intact nervous system, In: Castellano-López B and Nieto-Sampedro M (Eds.),Glial Cell Function (Progress in Brain Research), pp 481–498.

  • Carmeliet P (2001) Biomedicine. Clotting factors build blood vessels.Science 293, 1602–1604.

    Article  PubMed  CAS  Google Scholar 

  • Carreno-Muller E, AJ Herrera, RM de Pablos, M Tomas-Camardiel, JL Venero, J Cano and A Machado (2003) Thrombin inducesin vivo degeneration of nigral dopaminergic neurones along with the activation of microglia.J. Neurochem. 84, 1201–1214.

    Article  PubMed  CAS  Google Scholar 

  • Corbin JG, D Kelly, EM Rath, KD Baerwald, K Suzuki and B Popko (1996) Targeted CNS expression of interferon-γ in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development.Mol. Cell. Neurosci. 7, 354–370.

    Article  PubMed  CAS  Google Scholar 

  • Czlonkowska A, M Kohutnicka, I Kurkowska-Jastrzebska and A Czlonkowski (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model.Neurodegeneration 5, 137–143.

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, CJ Carter, FR Wells, F Javoy-Agid, Y Agid, A Lees, P Jenner and CD Marsden (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease.J. Neurochem. 52, 381–389.

    Article  PubMed  CAS  Google Scholar 

  • Dvorak HF, LF Brown, M Detmar and AM Dvorak (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.Am. J. Pathol. 146, 1029–1039.

    PubMed  CAS  Google Scholar 

  • Egwuagu CE, J Sztein, CC Chan, R Mahdi, RB Nussenblatt and AB Chepelinsky (1994) γ interferon expression disrupts lens and retinal differentiation in transgenic mice.Dev. Biol. 166, 557–568.

    Article  PubMed  CAS  Google Scholar 

  • Eriksson U and K Alitalo (1999) Structure, expression and receptor-binding properties of novel vascular endothelial growth factors.Curr. Top. Microbiol. Immunol. 237, 41–57.

    PubMed  CAS  Google Scholar 

  • Fargeas C, CY Wu, T Nakajima, D Cox, T Nutman and G Delespesse (1992) Differential effect of transforming growth factor beta on the synthesis of Th1- and Th2-like lymphokines by human T lymphocytes.Eur. J. Immunol. 22, 2173–2176.

    Article  PubMed  CAS  Google Scholar 

  • Faucheux BA, AM Bonnet, Y Agid and EC Hirsch (1999) Blood vessels change in the mesencephalon of patients with Parkinson's disease.Lancet 353, 981–982.

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N (1999) Molecular and biological properties of vascular endothelial growth factor.J. Mol. Med. 77, 527–543.

    Article  PubMed  CAS  Google Scholar 

  • Fiers W (1991) Tumor necrosis factor. Characterization at the molecular, cellular andin vivo level.FEBS. Lett. 285, 199–212.

    Article  PubMed  CAS  Google Scholar 

  • Geiger K, E Howes, M Gallina, XJ Huang, GH Travis and N Sarvetnick (1994) Transgenic mice expressing IFN-γ in the retina develop inflammation of the eye and photoreceptor loss.Invest. Ophthalmol. Vis. Sci. 35, 2667–2681.

    PubMed  CAS  Google Scholar 

  • Giulian D and LB Lachman (1985) Interleukin-1 stimulation of astroglial proliferation after brain injury.Science 228, 497–499.

    Article  PubMed  CAS  Google Scholar 

  • Gotz ME, G Kunig, P Riederer and MB Youdim (1994) Oxidative stress: free radical production in neural degeneration.Pharmacol. Ther. 63, 37–122.

    Article  PubMed  CAS  Google Scholar 

  • Graeber MB, KB Bise and P Mehraein (1994) CR 3/43, a marker for activated microglia: aplication to diagnostic neuropathology.Neuropathol. Appl. Neurobiol. 20, 406–408.

    Article  PubMed  CAS  Google Scholar 

  • Hickey WF (1991) Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation.Brain. Pathol. 1, 97–105.

    Article  PubMed  CAS  Google Scholar 

  • Hirsch EC, S Hunot, P Damier and B Faucheux (1998) Glial cells and inflammation in Parkinson's disease: a role in neurodegeneration?Ann. Neurol. 44, 115–120.

    Google Scholar 

  • Horwitz MS, CF Evans, FG Klier and MB Oldstone (1999) Detailedin vivo analysis of interferon-γ induced major histocompatibility complex expression in the the central nervous system: astrocytes fail to express major histocompatibility complex class I and II molecules.Lab. Invest. 79, 235–242.

    PubMed  CAS  Google Scholar 

  • Hunot S, C Betard, B Faucheux, Y Agid and EC Hirsch (1997) Immunohistochemical analysis of interferon-γ and interleukin-1 beta in substantia nigra of Parkinsonian patients.Mov. Disord. 12, 20 [abstract].

    Google Scholar 

  • Hunot S and EC Hirsch (2003) Neuroinflammatory processes in Parkinson's disease.Ann. Neurol. 3, 49–58

    Article  Google Scholar 

  • Jain RK, GC Koenig, M Dellian, D Fukumura, LL Munn and RJ Melder (1996) Leukocyte-endothelial adhesion and angiogenesis in tumors.Cancer Metastasis Rev. 15, 195–204.

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz AA, WD Lyman, MP Guida, TM Calderon and JW Berman (1992) Tumor necrosis factor α induces adhesion molecule expression on human fetal astrocytes.J. Exp. Med. 176, 1631–1636.

    Article  PubMed  CAS  Google Scholar 

  • Jenner P and CW Olanow (1998) Understanding cell death in Parkinson's disease.Ann. Neurol. 44, 72–84.

    Google Scholar 

  • Kerbel RS (2000) Tumor angiogenesis: past, present and the near future.Carcinogenesis 21, 505–515.

    Article  PubMed  CAS  Google Scholar 

  • Kreutzberg GM (1996) Microglia signalling in neuropathology.Trends. Neurosci. 19, 312–318.

    Article  PubMed  CAS  Google Scholar 

  • Kiefer R, D Lindholm and GW Kreutzberg (1993) Interleukin-6 and transforming growth factor-beta 1 mRNAs are induced in rat facial nucleus following motoneuron axotomy.Eur. J. Neurosci. 5, 775–781.

    Article  PubMed  CAS  Google Scholar 

  • Kurkowska-Jastrzebska I, A Wronska, M Kohutnicka, A Czlonkowski and A Czlonkowska (1999) The inflammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse.Exp. Neurol. 156, 50–61.

    Article  PubMed  CAS  Google Scholar 

  • Langston JW, LS Forno, J Tetrud, AG Reeves, JA Kaplan and D Karluk (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure.Ann. Neurol. 46, 598–605.

    Article  PubMed  CAS  Google Scholar 

  • Le W, D Rowe, W Xie, I Ortiz, Y He and SH Appel (2001) Microglial activation and dopaminergic cell injury: anin vitro model relevant to Parkinson's disease.J. Neurosci. 21, 8447–8455.

    PubMed  CAS  Google Scholar 

  • Lee S, W Liu, D Dickson, C Brosnan and J Berman (1993) Cytokine production by human foetal microglia and astrocytes. Differential induction by lipopolisacharides and IL-1β.J. Immunol. 150, 2629–2667.

    Google Scholar 

  • Liu B and JS Hong (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention.J. Pharmacol. Exp. Ther. 304, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Liya Y and A Neufeld (2000) Tumor necrosis factor-α: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head.Glia 32, 42–50.

    Article  Google Scholar 

  • Loughlin AJ, MN Woodroofe and ML Cuzner (1993) Modulation of interferon-γ-induced major histocompatibility complex class II and Fc receptor expression on isolated microglia by transforming growth factor-beta 1, interleukin-4, noradrenaline and glucocorticoids.Immunology 79, 125–130.

    PubMed  CAS  Google Scholar 

  • McGeer PL, S Itagaki, BE Boyes and EG McGeer (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains.Neurology 38, 1285–1291.

    PubMed  CAS  Google Scholar 

  • McGeer PL, K Yasojima and EG McGeer (2001) Inflammation in Parkinson's disease.Adv. Neurol. 86, 83–89.

    PubMed  CAS  Google Scholar 

  • Merrill JE and EN Benveniste (1996) Cytokines in inflammatory brain lesions: helpful and harmful.Trends Neurosci. 19, 331–338.

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, M Harada, P Riederer, H Narabayashi, K Fujita and T Nagatsu (1994) Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients.Neurosci. Lett. 165, 208–210.

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, M Harada, H Narabayashi, H Inagaki, M Minami and T Nagatsu (1996) Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease.Neurosci. Lett. 211, 13–16.

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, A Togari, K Tanaka, N Ogawa, H Ichinose and T Nagatsu (1999) Increase in level of tumor necrosis factor (TNF)-α in 6-hydroxydopamine-lesioned striatum in rats without influence of systemic L-DOPA on the TNF-α induction.Neurosci. Lett. 268, 101–104.

    Article  PubMed  CAS  Google Scholar 

  • Pinedo HM, HM Verheul, RJ D'Amato and J Folkman (1998) Involvement of platelets in tumour angiogenesis?Lancet 352, 1775–1777.

    Article  PubMed  CAS  Google Scholar 

  • Renno T, V Taupin, L Bourbonniere, G Verge, E Tran, R De Simone, M Krakowski, M Rodriguez, A Peterson and T Owens (1998) Interferon-γ in progression to chronic demyelination and neurological deficit following acuteEAE.Mol. Cell. Neurosci. 12, 376–389.

    Article  PubMed  CAS  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis.Nature 386, 671–674.

    Article  PubMed  CAS  Google Scholar 

  • Rosenman SJ, P Shrikant, L Dubb, EN Benveniste and RM Ransohoff (1995) Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines.J. Immunol. 154, 1888–1899.

    PubMed  CAS  Google Scholar 

  • Rothwell NJ and SJ Hopkins (1995) Cytokines and the nervous system II: Actions and mechanisms of action.Trends Neurosci. 18, 130–136.

    Article  PubMed  CAS  Google Scholar 

  • Saez Cassanelli JL, C Barcia, V García-Martínez, JM Navarro-Ruiz and MT Herrero (2002) Increase of blood vessels in substantia nigra pars compacta in acute MPTP-treated mice. Relation with neuronal loss.Fens Forum p476 [Abstract].

  • Seljelid R, S Jozefowski and B Sveinbjornsson (1999) Tumor stroma.Anticancer Res. 19, 4809–4822.

    PubMed  CAS  Google Scholar 

  • Stone J, A Itin, T Alon, J Pe'er, H Gnessin, T Chan-Ling and E Keshet (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia.J. Neurosci. 15, 4738–4747.

    PubMed  CAS  Google Scholar 

  • Stypula G, J Kunert-Radek, H Stepien, K Zylinska and M Pawlikowski (1996) Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson's disease.Neuroimmunomodulation 3, 131–134.

    Article  PubMed  CAS  Google Scholar 

  • Tani M and RM Ransohoff (1994) Do chemokines mediate inflammatory cell invasion of the central nervous system parenchyma?Brain Pathol. 4, 135–143.

    Article  PubMed  CAS  Google Scholar 

  • Taupin V, T Renno, L Bourbonniere, AC Peterson, M Rodriguez and T Owens (1997) Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-α in the central nervous system.Eur. J. Immunol. 27, 905–913.

    Article  PubMed  CAS  Google Scholar 

  • Teismann P and B Ferger (2001) Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease.Synapse 39, 167–174.

    Article  PubMed  CAS  Google Scholar 

  • Teismann P, K Tieu, DK Choi, DC Wu, A Naini, S Hunot, M Vila, V Jackson-Lewis and S Przedborski (2003a) Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration.Proc. Natl. Acad. Sci. USA 100, 5473–5478.

    Article  PubMed  CAS  Google Scholar 

  • Teismann P, K Tieu, O Cohen, DK Choi, du C Wu, D Marks, M Vila, V Jackson-Lewis and S Przedborski (2003b) Pathogenic role of glial cells in Parkinson's disease.Mov. Disord. 18, 121–129.

    Article  PubMed  Google Scholar 

  • Tyor WR, JD Glass, N Baumrind, JC McArthur, JW Griffin, PS Becker and DE Griffin (1993) Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy.Neurology 43, 1002–1009.

    PubMed  CAS  Google Scholar 

  • Van Dam AM, J Bauer, FJ Tilders and F Berkenbosch (1995) Exdotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: a light and electron microscopic study.Neuroscience 65, 815–826.

    Article  PubMed  Google Scholar 

  • Wilms H, P Rosenstiel, J Sievers, G Deuschl, L Zecca and R Lucius (2003) Activation of microglia by human neuromelanin is NF-kappaB dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson's disease.FASEB J. 17, 500–502.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Experimental Neurology and Neurosurgery Group, School of Medicine, Campus Espinardo, University of Murcia, 30071, Murcia, Spain

    Carlos Barcia, Andrés Fernández Barreiro, Máximo Poza & María-Trinidad Herrero

  2. Department of Human Anatomy and Psychobiology, School of Medicine, Campus Espinardo, University of Murcia, 30071, Murcia, Spain

    Carlos Barcia & María-Trinidad Herrero

  3. Department of Neurology, Hospital Virgen de la Arrixaca, Murcia, Spain

    Andrés Fernández Barreiro

  4. Department of Neurosurgery, Hospital Virgen de la Arrixaca, Murcia, Spain

    Máximo Poza

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  1. Carlos Barcia
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Correspondence to Carlos Barcia or María-Trinidad Herrero.

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Barcia, C., Barreiro, A.F., Poza, M. et al. Parkinson's disease and inflammatory changes. neurotox res 5, 411–417 (2003). https://doi.org/10.1007/BF03033170

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