Down-regulation of microglial activity attenuates axotomized nigral dopaminergic neuronal cell loss

BMC Neuroscience

Tai-Kyoung Baik¹  Byung-Pil Cho²  Jung-Tae Han¹  Ran-Sook Woo¹  Byung-Gu Park²  Ji-Yong Lee²  Jin-Sook Lee²  Chae-Ri Park¹  Ha-Nul Yu¹  Dae-Yong Song¹ 

[1] Department of Anatomy and Neuroscience, Eulji University School of Medicine, 143-5, Yongdu-dong, 301-832 Jung-gu, Daejeon, Republic of KoreaKorea;Department of Anatomy and Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea

关键词: Tuftsin fragment 1-3;    Reactive oxygen species;    Activated microglia;    Axotomy;    Medial forebrain bundle (MFB);   

Others  :  1140036
DOI  :  10.1186/1471-2202-14-112

 received in 2013-03-12, accepted in 2013-09-26,  发布年份 2013

【 摘 要 】

Background

There is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective.

Results

The transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased.

Conclusion

The present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.

【 授权许可】

   
2013 Song et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lawson LJ, Perry VH, Dri P, Gordon S: Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 1990, 39:151-170.
• [2]Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996, 19:312-318.
• [3]Streit WJ, Kreutzberg GW: Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J Comp Neurol 1988, 268:248-263.
• [4]Graeber MB, Streit WJ, Kreutzberg GW: Axotomy of the rat facial nerve leads to increased CR3 complement receptor expression by activated microglial cells. J Neurosci Res 1988, 21:18-24.
• [5]Kaur C, Ling EA: Activation and re-expression of surface antigen in microglia following an epidural application of kainic acid in the rat brain. J Anat 1992, 180:333-342.
• [6]Rogers J, Luber-Narod J, Styren SD, Civin WH: Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 1988, 9:339-349.
• [7]Matsumoto Y, Ohmori K, Fujiwara M: Microglial and astroglial reactions to inflammatory lesions of experimental autoimmune encephalomyelitis in the rat central nervous system. J Neuroimmunol 1992, 37:23-33.
• [8]Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C: Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia 1993, 7:75-83.
• [9]Raine CS: Multiple sclerosis: immune system molecule expression in the central nervous system. J Neuropathol Exp Neurol 1994, 53:328-337.
• [10]Streit WJ: Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 2006, 29:506-510.
• [11]Hirsch EC, Hunot S: Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 2009, 8:382-397.
• [12]Liu B: Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease. Aaps J 2006, 8:606-621.
• [13]Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I, Czlonkowski A, Czlonkowska A: Microglial and astrocytic involvement in Parkinson’s disease mice model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 1998, 39:167-180.
• [14]He Y, Appel S, Le W: Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 2001, 909:187-193.
• [15]Rodrigues RW, Gomide VC, Chadi G: Astroglial and microglial reaction after a partial nigrostriatal degeneration induced by the striatal injection of different doses of 6-hydroxydopamine. Int J Neurosci 2001, 109:91-126.
• [16]Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S: 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.
• [17]Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O: Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 2002, 15:991-998.
• [18]Herrera AJ, Castano A, Venero JL, Cano J, Machado A: The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis 2000, 7:429-447.
• [19]Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT: Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007, 55:453-462.
• [20]Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. PNAS 2003, 100:8514-8519.
• [21]Liu B, Du L, Hong JS: Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther 2000, 293:607-617.
• [22]Tomas-Camardiel M, Rite I, Herrera AJ, De Pablos RM, Cano J, Machado A, Venero JL: Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood–brain barrier, and damage in the nigral dopaminergic system. Neurobiol Dis 2004, 16:190-201.
• [23]Chen H, Zhang SM, Hernan MA, Schwarzschild MA, Willett WC, Colditz GA, Speizer FE, Ascherio A: Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 2003, 60:1059-1064.
• [24]Wahner AD, Bronstein JM, Bordelon YM, Ritz B: Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 2007, 69:1836-1842.
• [25]Becker C, Jick SS, Meier CR: NSAID use and risk of Parkinson disease: a population-based case–control study. Eur J Neurol 2011, 18:1336-1342.
• [26]Song DY, Yang YC, Shin DH, Sugama S, Kim YS, Lee BH, Joh TH, Cho BP: Axotomy-induced dopaminergic neurodegeneration is accompanied with c-Jun phosphorylation and activation transcription factor 3 expression. Exp Neurol 2008, 209:268-278.
• [27]Thanos S, Naskar R, Heiduschka P: Regenerating ganglion cell axons in the adult rat establish retinofugal topography and restore visual function. Exp Brain Res 1997, 114:483-491.
• [28]Wang J, Rogove AD, Tsirka AE, Tsirka SE: Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol 2003, 54:655-664.
• [29]Wang J, Tsirka SE: Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 2005, 36:613-618.
• [30]Brewer GJ, Torricelli JR: Isolation and culture of adult neurons and neurospheres. Nat Protoc 2007, 2:1490-1498.
• [31]Paxinos G, Watson C: The rat brain in stereotaxic coordinates. SanDiego: Academic Press; 1998.
• [32]Damoiseaux JG, Dopp EA, Calame W, Chao D, MacPherson GG, Dijkatra CD: Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology 1994, 83:140-147.
• [33]Bindokas VP, Jordan J, Lee CC, Miller RJ: Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 1996, 16:1324-1336.
• [34]Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. PNAS 2003, 100:6145-6150.
• [35]Kirik D, Rosenblad C, Bjorklund A: Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 1998, 152:259-277.
• [36]Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
• [37]Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983, 219:979-980.
• [38]Ballard PA, Tetrud JW, Langston JW: Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985, 35:949-956.
• [39]Ungerstedt U: Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 1971, 367:95-122.
• [40]Reis DJ, Ross RA: Dynamic changes in brain dopamine-beta-hydroxylase activity during anterograde and retrograde reactions to injury of central noradrenergic axons. Brain Res 1973, 57:307-326.
• [41]Nicklas WJ, Vyas I, Heikkila RE: Inhibition of NADHlinked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Life Sci 1985, 36:2503-2508.
• [42]Cho BP, Song DY, Sugama S, Shin DH, Shimizu Y, Kim SS, Kim YS, Joh TH: Pathological dynamics of activated microglia following medial forebrain bundle transection. Glia 2006, 53:92-102.
• [43]Spooren WP, Gentsch C, Wiessner C: TUNEL-positive cells in the substantia nigra of C57BL/6 mice after a single bolus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 1998, 85:649-651.
• [44]Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, Hirsch EC: Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. PNAS 2000, 97:2875-2880.
• [45]Venero JL, Revuelta M, Cano J, Machado A: Time course changes in the dopaminergic nigrostriatal system following transection of the medial forebrain bundle: detection of oxidatively modified proteins in substantia nigra. J Neurochem 1997, 68:2458-2468.
• [46]Liu L, Hsu SS, Kalia SK, Lozano AM: Injury and strain-dependent dopaminergic neuronal degeneration in the substantia nigra of mice after axotomy or MPTP. Brain Res 2003, 994:243-352.
• [47]Cho BP, Sugama S, Shin DH, DeGiorgio LA, Kim SS, Kim YS, Lim SY, Park KC, Volpe BT, Cho S, Joh TH: Microglial phagocytosis of dopamine neurons at early phases of apoptosis. Cell Mol Neurobiol 2003, 23:551-560.
• [48]Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M: Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 1998, 18:5124-5135.
• [49]Bucana C, Saiki I, Nayar R: Uptake and accumulation of the vital dye hydroethidine in neoplastic cells. J Histochem Cytochem 1986, 34:1109-1115.
• [50]Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS: Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci 2002, 962:318-331.
• [51]Cadet JL, Brannock C: Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 1998, 32:117-131.
• [52]Gehrmann J, Matsumoto Y, Kreutzberg GW: Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995, 20:269-287.
• [53]Floor E, Wetzel MG: Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J Neurochem 1998, 70:268-275.
• [54]Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD: Increased nigral iron content in postmortem parkinsonian brain. Lancet 1987, 21:1219-1220.
• [55]Bharath S, Hsu M, Kaur D, Rajagopalan S, Andersen JK: Glutathione, iron and Parkinson’s disease. Biochem Pharmacol 2002, 64:1037-1048.
• [56]Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS: Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 2000, 20:6309-6316.
• [57]De Jong EK, De Haas AH, Brouwer N, Van Weering HR, Hensens M, Bechmann I, Pratley P, Wesseling E, Boddeke HW, Biber K: Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J Neurochem 2008, 105:1726-1736.
• [58]Horvath RJ, Nutile-McMenemy N, Alkaitis MS, DeLeo JA: Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 2008, 107:557-569.
• [59]McCluskey LP, Lampson LA: Local neurochemicals and site-specific immune regulation in the CNS. J Neuropathol Exp Neurol 2000, 59:177-187.
• [60]Graeber MB, Li W, Rodriguez ML: Role of microglia in CNS inflammation. FEBS Lett 2011, 585:3798-3805.
• [61]Streit WJ, Graeber MB: Heterogeneity of microglial and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia 1993, 7:68-74.
• [62]Auriault C, Pestel J, Joseph M, Dessaint JP, Capron A: Interaction between macrophages and Schistosoma mansoni schistosomula: role of IgG peptides and aggregates on the modulation of beta-glucuronidase release and the cytotoxicity against schistosomula. Cell Immunol 1981, 62:15-27.
• [63]Thanos S, Mey J, Wild M: Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro. J Neurosci 1993, 13:455-466.
• [64]Aviles-Trigueros M, Sauve Y, Lund RD, Vidal-Sanz M: Selective innervation of retinorecipient brainstem nuclei by retinal ganglion cell axons regenerating through peripheral nerve grafts in adult rats. J Neurosci 2000, 20:361-374.