Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model

GLIA

Volumn 61, Issue 7, 2013, Pages 1084-1100

  Lazzarini, Marcio ^a   Martin, Sabine ^b,c   Mitkovski, Mišo ^b,c   Vozari, Rita Raisman ^d   Stühmer, Walter ^b,c   Bel, Elaine Del ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b MAX PLANCK INSTITUTE OF EXPERIMENTAL MEDICINE   (Germany)

^c Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)   (Germany)

^d INSTITUT DU CERVEAU ET DE LA MOELLE ÉPINIÈRE   (France)

Author keywords

6 OHDA Parkinson model; Astrocytes; Microglia; Neuroprotection; Tyrosine hydroxylase

Indexed keywords

CASPASE 3; CYCLOOXYGENASE 2; DOXYCYCLINE; STROMELYSIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASTROCYTE; BRAIN REGION; CIRCLING BEHAVIOR; CONTROLLED STUDY; DOPAMINERGIC NERVE CELL; GLIA; GLOBUS PALLIDUS; IN VIVO STUDY; MALE; MICROGLIA; MOUSE; NERVE DEGENERATION; NERVE ENDING; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN EXPRESSION; SUBSTANTIA NIGRA; SUBSTANTIA NIGRA PARS RETICULATA; TRANSGENE; VENTRAL TEGMENTUM;

ADRENERGIC AGENTS; ANALYSIS OF VARIANCE; ANIMALS; BRAIN; CYCLOOXYGENASE 2; DISEASE MODELS, ANIMAL; DOXYCYCLINE; GLIAL FIBRILLARY ACIDIC PROTEIN; MACROPHAGE-1 ANTIGEN; MALE; MATRIX METALLOPROTEINASE 3; MICE; MICE, INBRED C57BL; MOTOR ACTIVITY; NEUROGLIA; NEUROPROTECTIVE AGENTS; OXIDOPAMINE; PARKINSON DISEASE; TYROSINE 3-MONOOXYGENASE;

EID: 84879600602     PISSN: 08941491     EISSN: 10981136     Source Type: Journal    
DOI: 10.1002/glia.22496     Document Type: Article

References (159)

1. Aaron SD, Valenza F, Volgyesi G, Mullen JB, Slutsky AS, Stewart TE. Inhibition of exhaled nitric oxide production during sepsis does not prevent lung inflammation. Crit Care Med 1998;26:309-314.
2. Akiyama H, McGeer PL. Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res 1989;489:247-253.
3. Ambrosi G, Armentero MT, Levandis G, Bramanti P, Nappi G, Blandini F. Effects of early and delayed treatment with an mGluR5 antagonist on motor impairment, nigrostriatal damage and neuroinflammation in a rodent model of Parkinson's disease. Brain Res Bull 2010;82:29-38.
4. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB. A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc Natl Acad Sci USA 1996;93:14014-14019.
5. Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Abramson SB. Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett 1997;410:259-264.
6. Andersson H, Alestig K. The penetration of doxycycline into CSF. Scand J Infect Dis 1976;(Suppl):17-19.
7. Araque A, Carmignoto G, Haydon PG. Dynamic signaling between astrocytes and neurons. Annu Rev Physiol 2001;63:795-813.
8. Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 2002;52:54-61.
9. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov Disord 1998;13:221-227.
10. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. Cytotoxicity of microglia. Glia 1993;7:111-118.
11. Banker GA. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 1980;209:809-810.
12. Barza M, Brown RB, Shanks C, Gamble C, Weinstein L. Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother 1975;8:713-720.
13. Berkhout B, Verhoef K, Marzio G, Klaver B, Vink M, Zhou X, Das AT. Conditional virus replication as an approach to a safe live attenuated human immunodeficiency virus vaccine. J Neurovirol 2002;8 (Suppl 2):134-137.
14. Bjorklund L, Stromberg I. Dopaminergic innervation of striatal grafts placed into different sites of normal striatum: Differences in the tyrosine hydroxylase immunoreactive growth pattern. Exp Brain Res 1997;113:13-23.
15. Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson's disease. J Biomed Biotechnol 2012;2012:845618.
16. Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M. Clinical potential of minocycline for neurodegenerative disorders. Neurobiol Dis 2004;17:359-366.
17. Boyle JR, McDermott E, Crowther M, Wills AD, Bell PR, Thompson MM. Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease. J Vasc Surg 1998;27:354-361.
18. Bronstein DM, Perez-Otano I, Sun V, Mullis Sawin SB, Chan J, Wu GC, Hudson PM, Kong LY, Hong JS, McMillian MK. Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures. Brain Res 1995;704:112-116.
19. Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol 2004a;24:733-738.
20. Brown S, Meroueh SO, Fridman R, Mobashery S. Quest for selectivity in inhibition of matrix metalloproteinases. Curr Top Med Chem 2004b;4:1227-1238.
21. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis. Brain 2002;125 ( Part 6):1297-1308.
22. Bujas-Bobanovic M, Bird DC, Robertson HA, Dursun SM. Blockade of phencyclidine-induced effects by a nitric oxide donor. Br J Pharmacol 2000;130:1005-1012.
23. Burggraf D, Trinkl A, Dichgans M, Hamann GF. Doxycycline inhibits MMPs via modulation of plasminogen activators in focal cerebral ischemia. Neurobiol Dis 2007;25:506-513.
24. Castano A, Herrera AJ, Cano J, Machado A. Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem 1998;70:1584-1592.
25. Castano A, Herrera AJ, Cano J, Machado A. The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha, IL-1beta and IFN-gamma. J Neurochem 2002;81:150-157.
26. Cenci MA, Tranberg A, Andersson M, Hilbertson A. Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. Neuroscience 1999;94:515-527.
27. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000;6:797-801.
28. Cho Y, Son HJ, Kim EM, Choi JH, Kim ST, Ji IJ, Choi DH, Joh TH, Kim YS, Hwang O. Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3. Neurotox Res 2009;16:361-371.
29. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology 2007;32:2393-2404.
30. Clark WM, Calcagno FA, Gabler WL, Smith JR, Coull BM. Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment. Stroke 1994;25:1411-1415; discussion 1416.
31. Clark WM, Lessov N, Lauten JD, Hazel K. Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat. J Mol Neurosci 1997;9:103-108.
32. Czlonkowska A, Kohutnicka M, Kurkowska-Jastrzebska I, Czlonkowski A. Microglial reaction in MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) induced Parkinson's disease mice model. Neurodegeneration 1996;5:137-143.
33. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F. Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 1993;52:1-6.
34. Damier P, Kastner A, Agid Y, Hirsch EC. Does monoamine oxidase type B play a role in dopaminergic nerve cell death in Parkinson's disease? Neurology 1996;46:1262-1269.
35. de Meira Santos Lima M, Braga Reksidler A, Marques Zanata S, Bueno Machado H, Tufik S, Vital MA. Different parkinsonism models produce a time-dependent induction of COX-2 in the substantia nigra of rats. Brain Res 2006;1101:117-125.
36. Depino AM, Earl C, Kaczmarczyk E, Ferrari C, Besedovsky H, del Rey A, Pitossi FJ, Oertel WH. Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease. Eur J Neurosci 2003;18:2731-2742.
37. Diguet E, Fernagut PO, Wei X, Du Y, Rouland R, Gross C, Bezard E, Tison F. Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease. Eur J Neurosci 2004;19:3266-3276.
38. Domercq M, Matute C. Neuroprotection by tetracyclines. Trends Pharmacol Sci 2004;25:609-612.
39. Douhou A, Debeir T, Murer MG, Do L, Dufour N, Blanchard V, Moussaoui S, Bohme GA, Agid Y, Raisman-Vozari R. Effect of chronic treatment with riluzole on the nigrostriatal dopaminergic system in weaver mutant mice. Exp Neurol 2002;176:247-253.
40. Dreyer JL. Lentiviral vector-mediated gene transfer and RNA silencing technology in neuronal dysfunctions. Mol Biotechnol 2010;47:169-187.
41. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci USA 2001;98:14669-14674.
42. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA. Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem 2006;97:1314-1326.
43. Fitzsimons HL, McKenzie JM, During MJ. Insulators coupled to a minimal bidirectional tet cassette for tight regulation of rAAV-mediated gene transfer in the mammalian brain. Gene Ther 2001;8:1675-1681.
44. Furth PA, St Onge L, Boger H, Gruss P, Gossen M, Kistner A, Bujard H, Hennighausen L. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA 1994;91:9302-9306.
45. Gabler WL, Creamer HR. Suppression of human neutrophil functions by tetracyclines. J Periodontal Res 1991;26:52-58.
46. Gao HM, Hong JS. Gene-environment interactions: key to unraveling the mystery of Parkinson's disease. Prog Neurobiol 2008;94:1-19.
47. Garden GA, Moller T. Microglia biology in health and disease. J Neuroimmune Pharmacol 2006;1:127-137.
48. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 2006;21:404-412.
49. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010;140:918-934.
50. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR. Tetracyclines inhibit connective tissue breakdown: New therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 1991;2:297-321.
51. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12-26.
52. Gomes MZ, Raisman-Vozari R, Del Bel EA. A nitric oxide synthase inhibitor decreases 6-hydroxydopamine effects on tyrosine hydroxylase and neuronal nitric oxide synthase in the rat nigrostriatal pathway. Brain Res 2008;1203:160-169.
53. Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science 1995;268:1766-1769.
54. Ham A, Lee SJ, Shin J, Kim KH, Mar W. Regulatory effects of costunolide on dopamine metabolism-associated genes inhibit dopamine-induced apoptosis in human dopaminergic SH-SY5Y cells. Neurosci Lett 2012;507:101-105.
55. Hanisch UK, Kettenmann H. Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007;10:1387-1394.
56. 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.
57. He Y, Lee T, Leong SK. 6-Hydroxydopamine induced apoptosis of dopaminergic cells in the rat substantia nigra. Brain Res 2000;858:163-166.
58. Heales SJ, Lam AA, Duncan AJ, Land JM. Neurodegeneration or neuroprotection: The pivotal role of astrocytes. Neurochem Res 2004;29:513-519.
59. Henning J, Strauss U, Wree A, Gimsa J, Rolfs A, Benecke R, Gimsa U. Differential astroglial activation in 6-hydroxydopamine models of Parkinson's disease. Neurosci Res 2008;62:246-253.
60. Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 2008;5:15.
61. Heo K, Cho YJ, Cho KJ, Kim HW, Kim HJ, Shin HY, Lee BI, Kim GW. Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci Lett 2006;398:195-200.
62. Hirsch EC, Hunot S. Nitric oxide, glial cells and neuronal degeneration in parkinsonism. Trends Pharmacol Sci 2000;21:163-165.
63. Hirsch EC, Hunot S, Damier P, Brugg B, Faucheux BA, Michel PP, Ruberg M, Muriel MP, Mouatt-Prigent A, Agid Y. Glial cell participation in the degeneration of dopaminergic neurons in Parkinson's disease. Adv Neurol 1999;80:9-18.
64. Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinson's disease: A role in neurodegeneration?Ann Neurol 1998;44:S115-S120.
65. Hou JG, Cohen G, Mytilineou C. Basic fibroblast growth factor stimulation of glial cells protects dopamine neurons from 6-hydroxydopamine toxicity: Involvement of the glutathione system. J Neurochem 1997;69:76-83.
66. Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 2004;19:3305-3316.
67. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S. Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Neurodegeneration 1995;4:257-269.
68. Jantzie LL, Cheung PY, Todd KG. Doxycycline reduces cleaved caspase-3 and microglial activation in an animal model of neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 2005;25:314-324.
69. Jantzie LL, Rauw GA, Todd KG. The effects of doxycycline administration on amino acid neurotransmitters in an animal model of neonatal hypoxia-ischemia. Neurochem Int 2006;49:717-728.
70. Jantzie LL, Todd KG. Doxycycline inhibits proinflammatory cytokines but not acute cerebral cytogenesis after hypoxia-ischemia in neonatal rats. J Psychiatry Neurosci 2010;35:20-32.
71. Kelly KJ, Sutton TA, Weathered N, Ray N, Caldwell EJ, Plotkin Z, Dagher PC. Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. Am J Physiol Renal Physiol 2004;287:F760-F766.
72. Kim HS, Luo L, Pflugfelder SC, Li DQ. Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2005;46:840-848.
73. Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009;196:168-179.
74. Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease. J Endocrinol 2009;202:431-439.
75. 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.
76. Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H, Bujard H. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 1996;93:10933-10938.
77. Klein NC, Cunha BA. Tetracyclines. Med Clin North Am 1995;79:789-801.
78. Kleinhammer A, Deussing J, Wurst W, Kuhn R. Conditional RNAi in mice. Methods 2011;53:142-150.
79. Kofman O, van Embden S, Alpert C, Fuchs I. Central and peripheral minocycline suppresses motor activity in rats. Pharmacol Biochem Behav 1993;44:397-402.
80. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. 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 1999;46:598-605.
81. Lee CS, Sauer H, Bjorklund A. Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience 1996;72:641-653.
82. Lee H, Park JW, Kim SP, Lo EH, Lee SR. Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia. Neurobiol Dis 2009;34:189-198.
83. Lee SM, Yune TY, Kim SJ, Kim YC, Oh YJ, Markelonis GJ, Oh TH. Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co-cultures. J Neurochem 2004;91:568-578.
84. Lees AJ. Evidence-based efficacy comparison of tolcapone and entacapone as adjunctive therapy in Parkinson's disease. CNS Neurosci Ther 2008;14:83-93.
85. LeWitt PA. Clinical trials of neuroprotection for Parkinson's disease. Neurology 2004;63:S23-S31.
86. Liberatore GT, Finkelstein DI, Wong JY, Horne MK, Porritt MJ, Donnan GA, Howells DW. Sprouting of dopaminergic axons after striatal injury: Confirmation by markers not dependent on dopamine metabolism. Exp Neurol 1999a;159:565-573.
87. Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999b;5:1403-1409.
88. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003;304:1-7.
89. Liu Y, Qin L, Li G, Zhang W, An L, Liu B, Hong JS. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 2003;305:212-218.
90. Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 2007;10:1355-1360.
91. Lundblad M, Usiello A, Carta M, Hakansson K, Fisone G, Cenci MA. Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia. Exp Neurol 2005;194:66-75.
92. Macdonald H, Kelly RG, Allen ES, Noble JF, Kanegis LA. Pharmacokinetic studies on minocycline in man. Clin Pharmacol Ther 1973;14:852-861.
93. Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJ. Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: Evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 1994;62:45-53.
94. Mansuy IM, Winder DG, Moallem TM, Osman M, Mayford M, Hawkins RD, Kandel ER. Inducible and reversible gene expression with the rtTA system for the study of memory. Neuron 1998;21:257-265.
95. Martin S, Lino de Oliveira C, Mello de Queiroz F, Pardo LA, Stuhmer W, Del Bel E. Eag1 potassium channel immunohistochemistry in the CNS of adult rat and selected regions of human brain. Neuroscience 2008;155:833-844.
96. McGeer EG, McGeer PL. The role of the immune system in neurodegenerative disorders. Mov Disord 1997;12:855-858.
97. McGeer PL, McGeer EG. Glial cell reactions in neurodegenerative diseases: Pathophysiology and therapeutic interventions. Alzheimer Dis Assoc Disord 1998;12 (Suppl 2):S1-S6.
98. Mena MA, de Bernardo S, Casarejos MJ, Canals S, Rodriguez-Martin E. The role of astroglia on the survival of dopamine neurons. Mol Neurobiol 2002;25:245-263.
99. Miller G. Neuroscience: The dark side of glia. Science 2005;308:778-781.
100. Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ. Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: An open-label trial. Arch Neurol 2008;65:199-204.
101. Mirza B, Hadberg H, Thomsen P, Moos T. The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience 2000;95:425-432.
102. Morris BJ, Simpson CS, Mundell S, Maceachern K, Johnston HM, Nolan AM. Dynamic changes in NADPH-diaphorase staining reflect activity of nitric oxide synthase: Evidence for a dopaminergic regulation of striatal nitric oxide release. Neuropharmacology 1997;36:1589-1599.
103. Newman EA. Glial cell inhibition of neurons by release of ATP. J Neurosci 2003a;23:1659-1666.
104. Newman EA. New roles for astrocytes: Regulation of synaptic transmission. Trends Neurosci 2003b;26:536-542.
105. Padovan-Neto FE, Echeverry MB, Chiavegatto S, Del-Bel E. Nitric oxide synthase inhibitor improves de novo and long-term l-DOPA-induced dyskinesia in hemiparkinsonian rats. Front Syst Neurosci 2011;5:40.
106. Padovan-Neto FE, Echeverry MB, Tumas V, Del-Bel EA. Nitric oxide synthase inhibition attenuates L-DOPA-induced dyskinesias in a rodent model of Parkinson's disease. Neuroscience 2009;159:927-935.
107. Paemen L, Martens E, Norga K, Masure S, Roets E, Hoogmartens J, Opdenakker G. The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors. Biochem Pharmacol 1996;52:105-111.
108. Park CH, Shin TK, Lee HY, Kim SJ, Lee WS. Matrix metalloproteinase inhibitors attenuate neuroinflammation following focal cerebral ischemia in mice. Korean J Physiol Pharmacol 2011;15:115-122.
109. Paxinos G, Franklin KBJ.The mouse brain in stereotaxic coordinates, 2nd ed.San Diego:Academic Press;2001.
110. Politis M, Su P, Piccini P. Imaging of microglia in patients with neurodegenerative disorders. Front Pharmacol 2012;3:96.
111. Prall AK, Longo GM, Mayhan WG, Waltke EA, Fleckten B, Thompson RW, Baxter BT. Doxycycline in patients with abdominal aortic aneurysms and in mice: Comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg 2002;35:923-929.
112. Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 2007;25:392-400.
113. Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson's disease. Neurotherapeutics 2010;7:413-423.
114. Reasoner DK, Hindman BJ, Dexter F, Subieta A, Cutkomp J, Smith T. Doxycycline reduces early neurologic impairment after cerebral arterial air embolism in the rabbit. Anesthesiology 1997;87:569-576.
115. Redfern CH, Coward P, Degtyarev MY, Lee EK, Kwa AT, Hennighausen L, Bujard H, Fishman GI, Conklin BR. Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice. Nat Biotechnol 1999;17:165-169.
116. 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.
117. Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 2004;48:85-90.
118. Sagara JI, Miura K, Bannai S. Maintenance of neuronal glutathione by glial cells. J Neurochem 1993;61:1672-1676.
119. Sanchez B, Relova JL, Gallego R, Ben-Batalla I, Perez-Fernandez R. 1, 25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J Neurosci Res 2009;87:723-732.
120. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001;48:1393-1399; discussion 1399-1401.
121. Sanchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL, Isacson O. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease. J Neuroinflammation 2004;1:6.
122. Sauer H, Oertel WH. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: A combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 1994;59:401-415.
123. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A. Fiji: An open-source platform for biological-image analysis. Nat Methods 2012;9:676-682.
124. Schwarting RK, Huston JP. The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 1996;50:275-331.
125. Smeyne M, Jiao Y, Shepherd KR, Smeyne RJ. Glia cell number modulates sensitivity to MPTP in mice. Glia 2005;52:144-152.
126. Smilack JD. The tetracyclines. Mayo Clin Proc 1999;74:727-729.
127. Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, Bates GP, Hockly E. Minocycline and doxycycline are not beneficial in a model of Huntington's disease. Ann Neurol 2003;54:186-196.
128. Smith K, Leyden JJ. Safety of doxycycline and minocycline: A systematic review. Clin Ther 2005;27:1329-1342.
129. Smith VA, Khan-Lim D, Anderson L, Cook SD, Dick AD. Does orally administered doxycycline reach the tear film? Br J Ophthalmol 2008;92:856-859.
130. Soulet D, Rivest S. Microglia. Curr Biol 2008;18:R506-R508.
131. Sprengel R, Hasan MT. Tetracycline-controlled genetic switches. Handb Exp Pharmacol 2007;178:49-72.
132. Stark KL, Gross C, Richardson-Jones J, Zhuang X, Hen R. A novel conditional knockout strategy applied to serotonin receptors. Handb Exp Pharmacol 2007;178:347-363.
133. Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB, Steeves JD, Ramer MS, Tetzlaff W. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 2004;24:2182-2190.
134. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neuroprotective agent. Neuroscientist 2005;11:308-322.
135. Stromberg I, Bygdeman M, Goldstein M, Seiger A, Olson L. Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: Evidence for functional reinnervation. Neurosci Lett 1986;71:271-276.
136. Stromberg I, Gemma C, Vila J, Bickford PC. Blueberry- and spirulina-enriched diets enhance striatal dopamine recovery and induce a rapid, transient microglia activation after injury of the rat nigrostriatal dopamine system. Exp Neurol 2005;196:298-307.
137. Tang XN, Wang Q, Koike MA, Cheng D, Goris ML, Blankenberg FG, Yenari MA. Monitoring the protective effects of minocycline treatment with radiolabeled annexin V in an experimental model of focal cerebral ischemia. J Nucl Med 2007;48:1822-1828.
138. Teismann P, Schulz JB. Cellular pathology of Parkinson's disease: Astrocytes, microglia and inflammation. Cell Tissue Res 2004;318:149-161.
139. Thomas M, Le WD. Minocycline: Neuroprotective mechanisms in Parkinson's disease. Curr Pharm Des 2004;10:679-686.
140. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001;166:7527-7533.
141. Ting DT, Kyba M, Daley GQ. Inducible transgene expression in mouse stem cells. Methods Mol Med 2005;105:23-46.
142. Toth A, Lesser ML, Naus G, Brooks C, Adams D. Effect of doxycycline on pre-menstrual syndrome: A double-blind randomized clinical trial. J Int Med Res 1988;16:270-279.
143. Tsuji M, Wilson MA, Lange MS, Johnston MV. Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model. Exp Neurol 2004;189:58-65.
144. Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 2002;13:1067-1070.
145. Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S. The role of glial cells in Parkinson's disease. Curr Opin Neurol 2001;14:483-489.
146. Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J. Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation 2003;108:1487-1492.
147. Wagner B, Natarajan A, Grunaug S, Kroismayr R, Wagner EF, Sibilia M. Neuronal survival depends on EGFR signaling in cortical but not midbrain astrocytes. EMBO J 2006;25:752-762.
148. Walker DG, Lue LF. Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. J Neurosci Res 2005;81:412-425.
149. Walsh S, Finn DP, Dowd E. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 2011;175:251-261.
150. Wang PQ, Sun SG, Qiao X. Protective effects of doxycycline upon dopaminergic neuron in LPS-induced rat model of Parkinson's disease. Zhonghua Yi Xue Za Zhi 2009;89:1346-1350.
151. Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc Natl Acad Sci USA 2003;100:10483-10487.
152. 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.
153. Yang L, Sugama S, Chirichigno JW, Gregorio J, Lorenzl S, Shin DH, Browne SE, Shimizu Y, Joh TH, Beal MF, Albers DS. Minocycline enhances MPTP toxicity to dopaminergic neurons. J Neurosci Res 2003;74:278-285.
154. Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis. Antimicrob Agents Chemother 1985;28:347-348.
155. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004;3:744-751.
156. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998;95:15769-15774.
157. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 1999;96:13496-13500.
158. Yune TY, Lee JY, Jung GY, Kim SJ, Jiang MH, Kim YC, Oh YJ, Markelonis GJ, Oh TH. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci 2007;27:7751-7761.
159. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74-78.