Subscribe to RSS
DOI: 10.1055/s-0044-101608
Parkinson-Erkrankung und Neuroinflammation – Zelluläre Pathologie, Mechanismen und therapeutische Optionen
Parkinson’s disease and neuroinflammation – Cellular pathology, mechanisms and therapeutic optionsPublication History
eingereicht 08 January 2018
akzeptiert 23 January 2018
Publication Date:
17 July 2018 (online)
![](https://www.thieme-connect.de/media/fdn/2018S01/lookinside/thumbnails/10.1055s-0044-101608-1.jpg)
Zusammenfassung
Durch verfeinerte Untersuchungstechniken in der Neuropathologie, der präzisierten molekularen Charakterisierung von Biomaterialien und nuklearmedizinische Untersuchungen des ZNS bei Parkinson-Patienten sind sowohl in post mortem Analysen aber auch intravital zahlreiche Belege für eine relevante Beteiligung der Neuroinflammation zu finden. Nach Evaluation immer größerer und besser definierter Patienten-Kohorten hat sich zudem gezeigt, dass unterschiedliche neuroinflammatorische zelluläre Akteure involviert sind. Diese Zelltypen und ihre Funktionen wurden zum Verständnis der pathogenetischen Mechanismen der Parkinson-Erkrankung in Zellkultur- und Tiermodellen detailliert untersucht und bilden eine Grundlage für die Entwicklung translationaler therapeutischer Ansätze. In dieser Übersichtsarbeit wird der derzeitige Wissensstand über die Bedeutung der Neuroinflammation bei der Parkinson-Erkrankung mit Fokus auf die zelluläre Pathologie von Astrozyten, Mikroglia und T-Lymphozyten differenziert in Modellsystemen und beim Menschen dargestellt. Sich daraus ableitende therapeutische Optionen, deren humane Anwendbarkeit sowie das Potential zur Verlaufsbeeinflussung der Parkinson-Erkrankung sind enorm und werden abschließend diskutiert.
Abstract
Refined examination techniques in neuropathology, more precise molecular characterization of biomaterials, and nuclear medicine studies of the CNS in Parkinson's disease provide ample evidence for relevant involvement of neuroinflammation in both post-mortem and intravital analyses. By evaluating ever larger and better-defined patient cohorts, it has also been shown that different neuroinflammatory cellular actors are involved. These cell types and their functions have been extensively studied in cell culture and animal models to understand the pathogenetic mechanisms of Parkinson's disease and form a basis for the development of translational therapeutic approaches. This review presents the current state of knowledge on the importance of neuroinflammation in Parkinson's disease with a focus on the cellular pathology of astrocytes, microglia and T lymphocytes in model systems and in humans. The resulting therapeutic options, their human applicability and the potential for influencing the course of Parkinson's disease are enormous and will be discussed.
-
Literaturverzeichnis
- 1 Obeso JA, Stamelou M, Goetz CG. et al. Past, present, and future of Parkinson’s disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord 2017; 32: 1264-1310
- 2 Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinsons Dis 2017; 3: 3
- 3 Lazaro DF, Pavlou MAS, Outeiro TF. Cellular models as tools for the study of the role of alpha-synuclein in Parkinson’s disease. Exp Neurol 2017; 298: 162-171
- 4 Blesa J, Przedborski S. Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 2014; 8: 155
- 5 Cannon JR, Greenamyre JT. Neurotoxic in vivo models of Parkinson’s disease recent advances. Prog Brain Res 2010; 184: 17-33
- 6 Langston JW. The MPTP Story. J Parkinsons Dis 2017; 7: S11-S22
- 7 Tonges L, Frank T, Tatenhorst L. et al. Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 2012; 135: 3355-3370
- 8 Tatenhorst L, Tonges L, Saal KA. et al. Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease. J Neuropathol Exp Neurol 2014; 73 : 770-779
- 9 Sherer TB, Betarbet R, Testa CM. et al. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 2003; 23: 10756-10764
- 10 Chesselet MF, Richter F. Modelling of Parkinson’s disease in mice. Lancet Neurol 2011; 10: 1108-1118
- 11 Tatenhorst L, Eckermann K, Dambeck V. et al. Fasudil attenuates aggregation of alpha-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun 2016; 4: 39
- 12 Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 2009; 3: 31
- 13 Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 2010; 119: 7-35
- 14 Morales I, Sanchez A, Rodriguez-Sabate C. et al. The astrocytic response to the dopaminergic denervation of the striatum. J Neurochem 2016; 139: 81-95
- 15 Swarnkar S, Goswami P, Kamat PK. et al. Rotenone-induced neurotoxicity in rat brain areas: a study on neuronal and neuronal supportive cells. Neuroscience 2013; 230: 172-183
- 16 Haas SJ, Zhou X, Machado V. et al. Expression of Tgfbeta1 and Inflammatory Markers in the 6-hydroxydopamine Mouse Model of Parkinson’s Disease. Front Mol Neurosci 2016; 9: 7
- 17 Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I. et al. Microglial and astrocytic involvement in a murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 1998; 39: 167-180
- 18 Swarnkar S, Singh S, Goswami P. et al. Astrocyte activation: a key step in rotenone induced cytotoxicity and DNA damage. Neurochem Res 2012; 37: 2178-2189
- 19 Giasson BI, Duda JE, Quinn SM. et al. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53 T human alpha-synuclein. Neuron 2002; 34: 521-533
- 20 Gan L, Vargas MR, Johnson DA. et al. Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci 2012; 32: 17775-17787
- 21 Loria F, Vargas JY, Bousset L. et al. alpha-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 2017; 134: 789-808
- 22 Rostami J, Holmqvist S, Lindstrom V. et al. Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes. J Neurosci 2017; 37: 11835-11853
- 23 Soulet D. Rivest S. Microglia. Curr Biol 2008 18. : R506-508
- 24 Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007; 10: 1387-1394
- 25 Wolf SA, Boddeke HW, Kettenmann H. Microglia in Physiology and Disease. Annu Rev Physiol 2017; 79: 619-643
- 26 Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-1318
- 27 Wake H, Moorhouse AJ, Jinno S. et al. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009; 29: 3974-3980
- 28 Tang Y, Le W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol 2016; 53: 1181-1194
- 29 Subramaniam SR, Federoff HJ. Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease. Front Aging Neurosci 2017; 9: 176
- 30 Graeber MB. Changing face of microglia. Science 2010; 330 : 783-788
- 31 Hu X, Leak RK, Shi Y. et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 2015; 11: 56-64
- 32 Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 2016; 19: 987-991
- 33 Tay TL, Mai D, Dautzenberg J. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 2017; 20: 793-803
- 34 Prinz M, Erny D, Hagemeyer N. Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 2017; 18: 385-392
- 35 Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I. et al. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 1996; 5: 137-143
- 36 Wu DC, Jackson-Lewis V, Vila M. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002; 22: 1763-1771
- 37 Barcia C, Ros CM, Annese V. et al. ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo. Sci Rep 2012; 2: 809
- 38 Rodriguez-Pallares J, Parga JA, Munoz A. et al. Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. J Neurochem 2007; 103: 145-156
- 39 Sherer TB, Betarbet R, Kim JH. et al. Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett 2003; 341 : 87-90
- 40 Gao HM, Hong JS, Zhang W. et al. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 2002; 22: 782-790
- 41 Emmrich JV, Hornik TC, Neher JJ. et al. Rotenone induces neuronal death by microglial phagocytosis of neurons. FEBS J 2013; 280: 5030-5038
- 42 Lawana V, Singh N, Sarkar S. et al. Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System. J Neuroimmune Pharmacol 2017; 12 : 624-660
- 43 Watson MB, Richter F, Lee SK. et al. Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp Neurol 2012; 237: 318-334
- 44 Theodore S, Cao S, McLean PJ. et al. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 2008; 67: 1149-1158
- 45 Tofaris GK, Garcia Reitbock P, Humby T. et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. J Neurosci 2006; 26: 3942-3950
- 46 Rocha EM, De Miranda B, Sanders LH. Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis 2018; 109: 249-257
- 47 Lee EJ, Woo MS, Moon PG. et al. Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 2010; 185: 615-623
- 48 Hoenen C, Gustin A, Birck C. et al. Alpha-Synuclein Proteins Promote Pro-Inflammatory Cascades in Microglia: Stronger Effects of the A53 T Mutant. PLoS One 2016 11. e0162717
- 49 Blaylock RL. Parkinson’s disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration. Surg Neurol Int 2017; 8: 65
- 50 Sampson TR, Debelius JW, Thron T. et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 2016; 167: 1469-1480 e1412
- 51 Fakhoury M. Immune-mediated processes in neurodegeneration: where do we stand? J Neurol 2016 (263) 1683-1701
- 52 Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M. et al. MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson’s disease. Acta Neurobiol Exp (Wars) 1999; 59: 1-8
- 53 Benner EJ, Banerjee R, Reynolds AD. et al. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 2008; 3 : e1376
- 54 Martin HL, Santoro M, Mustafa S. et al. Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson’s disease. Glia 2016; 64: 386-395
- 55 Brochard V, Combadiere B, Prigent A. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 2009; 119: 182-192
- 56 Gonzalez H, Contreras F, Prado C. et al. Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J Immunol 2013; 190: 5048-5056
- 57 Sommer A, Fadler T, Dorfmeister E. et al. Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J Neuroinflammation 2016; 13: 174
- 58 Tonges L, Szego EM, Hause P. et al. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson’s disease. Front Aging Neurosci 2014; 6: 239
- 59 Shameli A, Xiao W, Zheng Y. et al. A critical role for alpha-synuclein in development and function of T lymphocytes. Immunobiology 2016; 221 : 333-340
- 60 Rizzo G, Copetti M, Arcuti S. et al. Accuracy of clinical diagnosis of Parkinson disease: A systematic review and meta-analysis. Neurology 2016; 86: 566-576
- 61 Lerche S, Heinzel S, Alves GW. et al. Aiming for Study Comparability in Parkinson’s Disease: Proposal for a Modular Set of Biomarker Assessments to be Used in Longitudinal Studies. Front Aging Neurosci 2016; 8: 121
- 62 Teunissen CE, Tumani H, Engelborghs S. et al. Biobanking of CSF: international standardization to optimize biomarker development. Clin Biochem 2014; 47: 288-292
- 63 Foix C, Nicolesco J. Cérébrale: Les Noyauz Gris Centraux Et La Région Mésencephalo-Soue-Optique. In SuiviD’Un Appendice Sur L’Anatomic Pathologique De La Maladie De Parkinson: Masson et Cie.; 1925
- 64 Lewy F. Zur pathologischen Anatomie der Paralysis agitans. Dtsch Z Nervenheilk 1913
- 65 Braak H, Braak E, Yilmazer D. et al. Nigral and extranigral pathology in Parkinson’s disease. J Neural Transm Suppl 1995; 46: 15-31
- 66 McGeer PL, McGeer EG. Glial reactions in Parkinson’s disease. Mov Disord 2008; 23: 474-483
- 67 Forno LS, DeLanney LE, Irwin I. et al. Astrocytes and Parkinson’s disease. Prog Brain Res 1992; 94: 429-436
- 68 Mirza B, Hadberg H, Thomsen P. et al. The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 2000; 95: 425-432
- 69 Mena MA. Garcia de Yebenes J. Glial cells as players in parkinsonism: the “good,” the “bad,” and the “mysterious” glia. Neuroscientist 2008; 14: 544-560
- 70 Liddelow SA, Guttenplan KA, Clarke LE. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541: 481-487
- 71 Saal KA, Galter D, Roeber S. et al. Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson’s Disease. Brain Pathol 2017; 27: 13-25
- 72 Song YJ, Halliday GM, Holton JL. et al. Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 2009; 68: 1073-1083
- 73 Braak H, Sastre M, Del Tredici K. Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 2007; 114: 231-241
- 74 Booth HDE, Hirst WD. Wade-Martins R. The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends Neurosci 2017; 40: 358-370
- 75 Bandopadhyay R, Kingsbury AE, Cookson MR. et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 2004; 127: 420-430
- 76 Neumann M, Muller V, Gorner K. et al. Pathological properties of the Parkinson’s disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick’s disease. Acta Neuropathol 2004; 107: 489-496
- 77 Kim JM, Cha SH, Choi YR. et al. DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression. Sci Rep 2016; 6: 28823
- 78 Solano SM, Miller DW, Augood SJ. et al. Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson’s disease. Ann Neurol 2000; 47: 201-210
- 79 Lee HJ, Suk JE, Patrick C. et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 2010; 285: 9262-9272
- 80 Gu XL, Long CX, Sun L. et al. Astrocytic expression of Parkinson’s disease-related A53 T alpha-synuclein causes neurodegeneration in mice. Mol Brain 2010; 3: 12
- 81 Miklossy J, Arai T, Guo JP. et al. LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol 2006; 65: 953-963
- 82 Henry AG, Aghamohammadzadeh S, Samaroo H. et al. Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet 2015; 24: 6013-6028
- 83 Manzoni C, Mamais A, Dihanich S. et al. Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta 2013; 1833: 2900-2910
- 84 McGeer PL, Itagaki S, Boyes BE. et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38: 1285-1291
- 85 Croisier E, Moran LB, Dexter DT. et al. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2005; 2: 14
- 86 Imamura K, Hishikawa N, Sawada M. et al. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 2003; 106: 518-526
- 87 Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 2011; 26: 6-17
- 88 Hunot S, Boissière F, Faucheux B. et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 1996; 72: 355-363
- 89 Knott C, Stern G, Wilkin GP. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 2000; 16: 724-739
- 90 Qin XY, Zhang SP, Cao C. et al. Aberrations in Peripheral Inflammatory Cytokine Levels in Parkinson Disease: A Systematic Review and Meta-analysis. JAMA Neurol 2016; 73: 1316-1324
- 91 Ouchi Y, Yoshikawa E, Sekine Y. et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 2005; 57: 168-175
- 92 Ouchi Y, Yagi S, Yokokura M. et al. Neuroinflammation in the living brain of Parkinson’s disease. Parkinsonism Relat Disord 2009; 15 Suppl 3 : S200-204
- 93 Stokholm MG, Iranzo A, Ostergaard K. et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol 2017; 16: 789-796
- 94 Jucaite A, Svenningsson P, Rinne JO. et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease. Brain 2015; 138: 2687-2700
- 95 McGeer PL, Itagaki S, Akiyama H. et al. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 1988; 24: 574-576
- 96 Saunders JA, Estes KA, Kosloski LM. et al. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J Neuroimmune Pharmacol 2012; 7: 927-938
- 97 Stevens CH, Rowe D, Morel-Kopp MC. et al. Reduced T helper and B lymphocytes in Parkinson’s disease. J Neuroimmunol 2012; 252: 95-99
- 98 Baba Y, Kuroiwa A, Uitti RJ. et al. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 2005; 11: 493-498
- 99 Hamza TH, Zabetian CP, Tenesa A. et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 2010; 42: 781-785
- 100 Kannarkat GT, Cook DA, Lee JK. et al. Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson’s Disease: An Observational and Case-Control Study. NPJ Parkinsons Dis 2015; 1
- 101 Sulzer D, Alcalay RN, Garretti F. et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 2017; 546: 656-661
- 102 Petrich de Marquesini LG. Fu J, Connor KJ. et al. IFN-gamma and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes. Diabetologia 2010; 53: 1451-1460
- 103 Parkinson Study Group S-PDI,. Schwarzschild MA. Ascherio A. et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol 2014 71. 141-150
- 104 Bakshi R, Zhang H, Logan R. et al. Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release. Neurobiol Dis 2015; 82: 574-579
- 105 Drinkut A, Tereshchenko Y, Schulz JB. et al. Efficient gene therapy for Parkinson’s disease using astrocytes as hosts for localized neurotrophic factor delivery. Mol Ther 2012; 20 : 534-543
- 106 Song JJ, Oh SM, Kwon OC. et al. Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model. J Clin Invest 2018; 128 : 463-482
- 107 Rivetti di Val Cervo P. Romanov RA. Spigolon G. et al. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nat Biotechnol 2017; 35: 444-452
- 108 Harms AS, Barnum CJ, Ruhn KA. et al. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol Ther 2011; 19: 46-52
- 109 Pisanu A, Lecca D, Mulas G. et al. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 2014; 71: 280-291
- 110 Faraco G, Pittelli M, Cavone L. et al. Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis 2009; 36: 269-279
- 111 Morales-Garcia JA, Susin C, Alonso-Gil S. et al. Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease. ACS Chem Neurosci 2013; 4: 350-360
- 112 Schwenkgrub J, Joniec-Maciejak I, Sznejder-Pacholek A. et al. Effect of human interleukin-10 on the expression of nitric oxide synthases in the MPTP-based model of Parkinson’s disease. Pharmacol Rep 2013; 65: 44-49
- 113 Fernandez-Suarez D, Celorrio M, Riezu-Boj JI. et al. Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol Aging 2014; 35: 2603-2616
- 114 Campolo M, Casili G, Biundo F. et al. The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson’s Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-kappaB/Nuclear Transcription Factor Related to NF-E2. Antioxid Redox Signal 2017; 27: 453-471
- 115 Thome AD, Harms AS, Volpicelli-Daley LA. et al microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J Neurosci 2016; 36: 2383-2390
- 116 Brahmachari S, Karuppagounder SS, Ge P. et al. c-Abl and Parkinson’s Disease: Mechanisms and Therapeutic Potential. J Parkinsons Dis 2017; 7: 589-601
- 117 Pena-Altamira E, Prati F, Massenzio F. et al. Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation. Expert Opin Ther Targets 2016; 20: 627-640
- 118 Stopschinski BE, Diamond MI. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 2017; 16: 323-332
- 119 Mao X, Ou MT, Karuppagounder SS. et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016; 353
- 120 Allen Reish HE, Standaert DG. Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 2015; 5: 1-19
- 121 Olanow CW, Kordower JH. Targeting alpha-Synuclein as a therapy for Parkinson’s disease: The battle begins. Mov Disord 2017; 32: 203-207
- 122 Kingwell K. Zeroing in on neurodegenerative alpha-synuclein. Nat Rev Drug Discov 2017; 16: 371-373