Abstract
Interferon-γ (IFN-γ) is a proinflammatory cytokine that activates glial cells. IFN-γ is increased in the plasma and brain of Parkinson’s disease patients, suggesting its potential role in the disease. We investigated whether the IFN-γ deficiency could interfere with nigrostriatal degeneration induced by the neurotoxin 6-hydroxydopamine, L-DOPA-induced dyskinesia, and the neuroinflammatory features as astrogliosis, microgliosis, and induced nitric oxide synthase (iNOS) immunoreactivity induced by L-DOPA treatment. Wild type (WT) and IFN-γ knockout (IFN-γ/KO) mice received unilateral striatal microinjections of 6-hydroxydopamine. Animals were sacrificed 1, 3, 7, and 21 days after lesions. Additional group of WT and IFN-γ/KO parkinsonian mice, after 3 weeks of neurotoxin injection, received L-DOPA (intraperitoneally, for 21 days) resulting in dyskinetic-like behavior. Tyrosine hydroxylase immunostaining indicated the starting of dopaminergic lesion since the first day past toxin administration, progressively increased until the third day when it stabilized. There was no difference in the lesion and L-DOPA-induced dyskinesia intensity between WT and IFN-γ/KO mice. Remarkably, IFN-γ/KO mice treated with L-DOPA presented in the lesioned striatum an increase of iNOS and glial fibrilary acid protein (GFAP) density, compared with the WT group. Morphological analysis revealed the rise of astrocytes and microglia reactivity in IFN-γ/KO mice exibiting dyskinesia. In conclusion, IFN-γ/KO mice presented an intensification of the inflammatory reaction accompanying L-DOPA treatment and suggest that iNOS and GFAP increase, and the activation of astrocytes and microglia induced afterward L-DOPA treatment was IFN-γ independent events. Intriguingly, IFN-γ absence did not affect the degeneration of dopaminergic neurons or LID development.
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References
Andersson M, Hilbertson A, Cenci MA (1999) Striatal fosB expression is causally linked with L-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease. Neurobiol Dis 6:461–474. https://doi.org/10.1006/nbdi.1999.0259
Arganda-Carreras I, Fernández-González R, Muñoz-Barrutia A, Ortiz-De-Solorzano C (2010) 3D reconstruction of histological sections: application to mammary gland tissue. Microsc Res Tech 73:1019–1029. https://doi.org/10.1002/jemt.20829
Aron Badin R, Spinnewyn B, Gaillard MC, Jan C, Malgorn C, van Camp N, Dollé F, Guillermier M, Boulet S, Bertrand A, Savasta M, Auguet M, Brouillet E, Chabrier PE, Hantraye P (2013) IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates. PLoS One, 8(1). https://doi.org/10.1371/journal.pone.0052680
Barcia C, Ros CM, Annese V 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:e142–e142. https://doi.org/10.1038/cddis.2011.17
Barnum CJ, Eskow KL, Dupre K et al (2008) Exogenous corticosterone reduces l-DOPA-induced dyskinesia in the hemi-parkinsonian rat: role for interleukin-1β. Neuroscience 156:30–41. https://doi.org/10.1016/j.neuroscience.2008.07.016
Blanchette J, Jaramillo M, Olivier M (2003) Signalling events involved in interferon-γ-inducible macrophage nitric oxide generation. Immunology 108:513–522. https://doi.org/10.1046/j.1365-2567.2003.01620.x
Blandini F, Levandis G, Bazzini E et al (2007) Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: New clues from an old model. Eur J Neurosci 25:397–405. https://doi.org/10.1111/j.1460-9568.2006.05285.x
Boi L, Pisanu A, Greig NH et al (2019) Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson’s disease. Mov Disord 34:1818–1830. https://doi.org/10.1002/mds.27799
Bortolanza M, Cavalcanti-Kiwiatkoski R, Padovan-Neto FE et al (2015) Glial activation is associated with l-DOPA induced dyskinesia and blocked by a nitric oxide synthase inhibitor in a rat model of Parkinson’s disease. Neurobiol Dis 73:377–387. https://doi.org/10.1016/j.nbd.2014.10.017
Bortolanza M, Padovan-Neto FE, Cavalcanti-Kiwiatkoski R, Dos Santos-Pereira M, Mitkovski M, Raisman-Vozari R, Del-Bel E (2015) Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson’s disease induced by L-DOPA? Philos Trans R Soc B Biol Sci 370(1672):1–13. https://doi.org/10.1098/rstb.2014.0190
Breidert T, Callebert J, Heneka MT et al (2002) Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624. https://doi.org/10.1046/j.1471-4159.2002.00990.x
Brodacki B, Staszewski J, Toczyłowska B, Kozłowska E, Drela N, Chalimoniuk M, Stepien A (2008) Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFα, and INFγ concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett 441(2):158–162. https://doi.org/10.1016/j.neulet.2008.06.040
Carta AR, Mulas G, Bortolanza M et al (2017) L-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role? Eur J Neurosci 45:73–91. https://doi.org/10.1111/ejn.13482
Castaño A, Herrera AJ, Cano J, Machado A (2002) Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem 70:1584–1592. https://doi.org/10.1046/j.1471-4159.1998.70041584.x
Cenci MA (2014) Presynaptic mechanisms of l-DOPA-induced dyskinesia: the findings, the debate, and the therapeutic implications. Front Neurol 5 242 https://doi.org/10.3389/fneur.2014.00242
Cenci MA, Lundblad M (2007) Ratings of L -DOPA-induced dyskinesia in the unilateral 6-OHDA lesion model of Parkinson’s disease in rats and mice. Curr Protoc Neurosci 41 https://doi.org/10.1002/0471142301.ns0925s41
Członkowska A, Kohutnicka M, Kurkowska-Jastrzębska I et al (1996) Microglial reaction in MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration 5:137–143. https://doi.org/10.1006/neur.1996.0020
Damier P, Hirsch E, Zhang P et al (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52:1–6. https://doi.org/10.1016/0306-4522(93)90175-F
Del-Bel E, Bortolanza M, Dos-Santos-Pereira M et al (2016) L-DOPA-induced dyskinesia in Parkinson’s disease: are neuroinflammation and astrocytes key elements? Synapse 70:479–500. https://doi.org/10.1002/syn.21941
Delgado M (2003) Inhibition of interferon (IFN) gamma-induced Jak-STAT1 activation in microglia by vasoactive intestinal peptide: inhibitory effect on CD40, IFN-induced protein-10, and inducible nitric-oxide synthase expression. J Biol Chem 278:27620–27629. https://doi.org/10.1074/jbc.M303199200
dos-Santos-Pereira M, da-Silva CA, Guimarães FS, Del-Bel E, (2016) Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: possible mechanism of action. Neurobiol Dis 94:179–195. https://doi.org/10.1016/j.nbd.2016.06.013
dos-Santos-Pereira M, Abreu GHD, Rocca J et al (2021) Contributive role of TNF-α to L-DOPA-induced dyskinesia in a unilateral 6-OHDA lesion model of Parkinson’s disease. Front Pharmacol 11 https://doi.org/10.3389/fphar.2020.6170852020.617085
Espadas I, Keifman E, Palomo-Garo C, Burgaz S, García C, Fernández-Ruiz J, Moratalla R (2020) Beneficial effects of the phytocannabinoid Δ9-THCV in L-DOPA-induced dyskinesia in Parkinson's disease. Neurobiol Dis 141:104892. https://doi.org/10.1016/j.nbd.2020.104892
Espejo C, Penkowa M, Sáez-Torres I et al (2001) Treatment with anti-interferon-γ monoclonal antibodies modifies experimental autoimmune encephalomyelitis in interferon-γ receptor knockout mice. Exp Neurol 172:460–468. https://doi.org/10.1006/exnr.2001.7815
Ferber IA, Brocke S, Taylor-Edwards C et al (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156:5–7
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81(6):1285–1297. https://doi.org/10.1046/j.1471-4159.2002.00928.x
Giocanti-Auregan A, Vacca O, Bénard R et al (2016) Altered astrocyte morphology and vascular development in dystrophin-Dp71-null mice. Glia 64:716–729. https://doi.org/10.1002/glia.22956
Hanisch UK (2013) Functional diversity of microglia - How heterogeneous are they to begin with? Front Cell Neurosci 7:65. https://doi.org/10.3389/fncel.2013.00065
Hindinger C, Bergmann CC, Hinton DR et al (2012) IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability. PLoS One 7:42088. https://doi.org/10.1371/journal.pone.0042088
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397
Huh E, Choi JG, Sim Y, Oh MS (2019) An integrative approach to treat Parkinson’s disease: Ukgansan complements L-Dopa by ameliorating dopaminergic neuronal damage and L-Dopa-induced dyskinesia in mice. Front Aging Neurosci 10:431. https://doi.org/10.3389/fnagi.2018.00431
Koziorowski D, Tomasiuk R, Szlufik S, Friedman A (2012) Inflammatory cytokines and NT-proCNP in Parkinson’s disease patients. Cytokine 60(3):762–766. https://doi.org/10.1016/j.cyto.2012.07.030
Krakowski M, Owens T (1996) Interferon-γ confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 26:1641–1646. https://doi.org/10.1002/eji.1830260735
Ling Z, Zhu Y, wai 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. Experimental Neurology 199(2):499–512. https://doi.org/10.1016/j.expneurol.2006.01.010
Litteljohn D, Mangano E, Shukla N, Hayley S (2009) Interferon-γ deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat. Neuroscience 164:1894–1906. https://doi.org/10.1016/j.neuroscience.2009.09.025
Lundblad M, Picconi B, Lindgren H, Cenci MA (2004) A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 16(1):110–123. https://doi.org/10.1016/j.nbd.2004.01.007
Mangalam AK, Luo N, Luckey D et al (2014) Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB1*0301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system. J Immunol 193:4859–4870. https://doi.org/10.4049/jimmunol.1302008
Mangano E, Litteljohn D, So R et al (2012) Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways. Neurobiol Aging 33:1411–1426. https://doi.org/10.1016/j.neurobiolaging.2011.02.016
Martinez AA, Morgese MG, Pisanu A et al (2015) Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats. Neurobiol Dis 74:295–304. https://doi.org/10.1016/j.nbd.2014.11.024
McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483. https://doi.org/10.1002/mds.21751
Mogi M, Harada M, Riederer P et al (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. https://doi.org/10.1016/0304-3940(94)90746-3
Mogi M, Harada M, Narabayashi H et al (1996) Interleukin (IL)-1β, 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. https://doi.org/10.1016/0304-3940(96)12706-3
Mogi M, Kondo T, Mizuno Y, Nagatsu T (2007) p53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain. Neurosci Lett 414:94–97. https://doi.org/10.1016/j.neulet.2006.12.003
Moran LB, Duke DC, Graeber MB (2007) The microglial gene regulatory network activated by interferon-gamma. Artic J Neuroimmunol. https://doi.org/10.1016/j.jneuroim.2006.10.023
Mount MP, Lira A, Grimes D et al (2007) Involvement of interferon-γ in microglial-mediated loss of dopaminergic neurons. J Neurosci 27:3328–3337. https://doi.org/10.1523/JNEUROSCI.5321-06.2007
Mulas G, Espa E, Fenu S et al (2016) Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous L-DOPA delivery in the 6-OHDA model of Parkinson’s disease. Exp Neurol 286:83–92. https://doi.org/10.1016/j.expneurol.2016.09.013
Muñoz A, Garrido-Gil P, Dominguez-Meijide A, Labandeira-Garcia JL (2014) Angiotensin type 1 receptor blockage reduces l-dopa-induced dyskinesia in the 6-OHDA model of Parkinson's disease. Involvement of vascular endothelial growth factor and interleukin-1β. Exp Neurol 261:720–732. https://doi.org/10.1016/j.expneurol.2014.08.019
Muñoz-Fernández M, Fresno M (1998) The role of tumour necrosis factor, interleukin 6, interferon-γ and inducible nitric oxide synthase in the development and pathology of the nervous system. Prog Neurobiol 56:307–340
Ottum PA, Arellano G, Reyes LI et al (2015) Opposing roles of interferon-gamma on cells of the central nervous system in autoimmune neuroinflammation. Front Immunol 6:539. https://doi.org/10.3389/fimmu.2015.00539
Paxinos G, Franklin KB (2001) The Mouse Brain in Stereotaxic Coordinates. Academic Press, San Diego
Padovan-Neto F, Echeverry M, Tumas V et al (2009) Nitric oxide synthase inhibition attenuates L-DOPA-induced dyskinesias in a rodent model of Parkinson’s disease. Neuroscience 159:927-935. https://doi.org/10.1016/j.neuroscience.2009.01.0342
Padovan-Neto F, Cavalcanti-Kiwiatkoviski R, Carolino ROG et al (2015) Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. Neuropharmacology 89:87-99.
Pavón N, Martín AB, Mendialdua et al (2006) ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biological psychiatry 59:64–74. https://doi.org/10.1016/j.biopsych.2005.05.044
Pawate S, Shen Q, Fan F, Bhat NR (2004) Redox regulation of glial inflammatory response to lipopolysaccharide and interferonγ. J Neurosci Res 77:540–551. https://doi.org/10.1002/jnr.20180
Picconi B, Centonze D, Håkansson K et al (2003) Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci 6:501–506. https://doi.org/10.1038/nn1040
Pisanu A, Boi L, Mulas G et al (2018) Neuroinflammation in l-DOPA-induced dyskinesia: beyond the immune function. J Neural Transm 125:1287–1297
Popko B, Corbin JG, Baerwald KD et al (1997) The effects of interferon-γ on the central nervous system. Mol Neurobiol 14:19–35. https://doi.org/10.1007/BF02740619
Rentsch P, Stayte S, Morris GP, Vissel B (2019) Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia. BMC Neurosci 20:5. https://doi.org/10.1186/s12868-019-0487-7
Rodrigues RWP, Gomide VC, Chadi G (2001) Astroglial and microglial reaction after a partial nigrostriatal degeneration induced by the striatal injection of different doses of 6-hydroxydopamine. Int J Neurosci 109:91–126. https://doi.org/10.3109/00207450108986528
Rostworowski M, Balasingam V, Chabot S et al (1997) Astrogliosis in the neonatal and adult murine brain post-trauma: elevation of inflammatory cytokines and the lack of requirement for endogenous interferon-γ. J Neurosci 17:3664–3674. https://doi.org/10.1523/jneurosci.17-10-03664.1997
Salim T, Sershen CL, May EE (2016) Investigating the role of TNF-α and IFN-γ activation on the dynamics of iNOS gene expression in lps stimulated macrophages PLoS One 11. https://doi.org/10.1371/journal.pone.0153289
Santini E, Heiman M, Greengard P et al (2009) Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci Signal 2:ra36–ra36. https://doi.org/10.1126/scisignal.2000308
Schallert T, Fleming SM, Leasure JL et al (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787. https://doi.org/10.1016/S0028-3908(00)00005-8
Schindelin J, Arganda-Carreras I, Frise E et al (2012) Fiji: An open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019
Solís O, Espadas I, Del-Bel EA, Moratalla R (2015) Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3-/- aphakia mice. Neurobiol Dis 73:49–59. https://doi.org/10.1016/j.nbd.2014.09.010
Speck AE, Schamne MG, S. Aguiar A et al (2019) Treadmill exercise attenuates l-DOPA-induced dyskinesia and increases striatal levels of glial cell-derived neurotrophic factor (GDNF) in hemiparkinsonian mice. Mol Neurobiol 56:2944–2951. https://doi.org/10.1007/s12035-018-1278-3
Stott SRW, Barker RA (2014) Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson’s disease. Eur J Neurosci 39:1042–1056. https://doi.org/10.1111/ejn.12459
Stypuła G, Kunert-Radek J, Stępień H et al (1996) Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with Parkinson’s disease. Neuroimmunomodulation 3:131–134. https://doi.org/10.1159/000097237
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. https://doi.org/10.1016/j.nbd.2009.11.004
Tansey MG, Mccoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. https://doi.org/10.1016/j.expneurol.2007.07.004
Tarakad A, Jankovic J (2017) Diagnosis and management of Parkinson’s disease. Semin Neurol 37:118–126. https://doi.org/10.1055/s-0037-1601888
Teema AM, Zaitone SA, Moustafa YM (2016) Ibuprofen or piroxicam protects nigral neurons and delays the development of l-dopa induced dyskinesia in rats with experimental Parkinsonism: influence on angiogenesis. Neuropharmacology 107:432–450. https://doi.org/10.1016/j.neuropharm.2016.03.034
Winkler C, Kirik D, Björklund A, Cenci MA (2002) L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of Parkinson’s disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 10:165–186. https://doi.org/10.1006/nbdi.2002.0499
Wu DC, Jackson-Lewis V, Vila M et al (2002) Blockade of microglial activation is neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-ttrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771. https://doi.org/10.1523/JNEUROSCI.22-05-01763.2002
Young K, Morrison H (2018) Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using imagej. J Vis Exp 2018 https://doi.org/10.3791/57648
Acknowledgements
The authors wish to thank Dr. André Luis Bombeiro for the helpful suggestions on this study and Célia Aparecida da Silva for the technical support.
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The authors received financial support and grants provided by the Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/25029-4), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 402658/2012-4). EDB is a CNPq research fellow. DPF was recipient of FAPESP fellowship 2017/14419-4.
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MZ and EDB designed this study. DPF carried out the animal experiments and molecular analysis. DPF performed the statistical analysis and provided the figures. DPF, EDB, and MZ wrote the manuscript. All authors read and approved the final manuscript.
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Ferrari, D.P., Bortolanza, M. & Del Bel, E. Interferon-γ Involvement in the Neuroinflammation Associated with Parkinson’s Disease and L-DOPA-Induced Dyskinesia. Neurotox Res 39, 705–719 (2021). https://doi.org/10.1007/s12640-021-00345-x
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DOI: https://doi.org/10.1007/s12640-021-00345-x