Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra

Journal of Neuroinflammation

Volumn 11, Issue 1, 2014, Pages

  Nadella, Rasajna ^a   Voutilainen, Merja H ^b   Saarma, Mart ^b   Gonzalez Barrios, Juan A ^c   Leon Chavez, Bertha A ^d   Jimnez, Judith Dueas M ^e   Jimnez, Sergio Dueas H ^e   Escobedo, Lourdes ^a   Martinez Fong, Daniel ^a  

^a DEPARTAMENTO DE FÍSICA   (Mexico)

^b UNIVERSITY OF HELSINKI   (Finland)

^c HOSPITAL REGIONAL 1 DE OCTUBRE   (Mexico)

^d BENEMÉRITA UNIVERSIDAD AUTÓNOMA DE PUEBLA   (Mexico)

^e UNIVERSITY OF GUADALAJARA   (Mexico)

Author keywords

Astrocytes; CDNF; Cytokines; NBRE promoter; Neurotrophic factor; NG2 cells; Nitrosative stress; Polyplex

Indexed keywords

CEREBRAL DOPAMINE NEUROTROPHIC FACTOR; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 1BETA; INTERLEUKIN 6; LIPID PEROXIDE; NEUROTROPHIC FACTOR; NITRITE; OXIDOPAMINE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; CDNF PROTEIN, HUMAN; NERVE GROWTH FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ASTROCYTE; CEREBRAL DOPAMINE NEUROTROPHIC FACTOR GENE; CONTROLLED STUDY; GENE EXPRESSION; GLIA CELL; MALE; MICROGLIA; NERVOUS SYSTEM INFLAMMATION; NITROSATIVE STRESS; NONHUMAN; PARKINSONISM; RAT; SUBSTANTIA NIGRA; ANIMAL; BIOSYNTHESIS; CHEMICALLY INDUCED; DRUG EFFECTS; GENETIC TRANSFECTION; GENETICS; HUMAN; INFLAMMATION; INTRACEREBROVENTRICULAR DRUG ADMINISTRATION; METABOLISM; WISTAR RAT;

ANIMALS; HUMANS; INFLAMMATION; INJECTIONS, INTRAVENTRICULAR; MALE; NERVE GROWTH FACTORS; OXIDOPAMINE; RATS; RATS, WISTAR; SUBSTANTIA NIGRA; TRANSFECTION;

EID: 84924858330     PISSN: None     EISSN: 17422094     Source Type: Journal    
DOI: 10.1186/s12974-014-0209-0     Document Type: Article

References (86)

1. Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, Peaire AE, Shridhar V, Smith DI, Kelly J, Durocher Y, Commissiong JW: MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 2003, 20:173-188.
2. Lindholm P, Voutilainen MH, Lauren J, Peranen J, Leppanen VM, Andressoo JO, Lindahl M, Janhunen S, Kalkkinen N, Timmusk T, Tuominen RK, Saarma M: Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo Nature 2007, 448:73-77.
3. Lindholm P, Peranen J, Andressoo JO, Kalkkinen N, Kokaia Z, Lindvall O, Timmusk T, Saarma M: MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci 2008, 39:356-371.
4. Airavaara M, Shen H, Kuo CC, Peranen J, Saarma M, Hoffer B, Wang Y: Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats. J Comp Neurol 2009, 515:116-124.
5. Voutilainen MH, Back S, Porsti E, Toppinen L, Lindgren L, Lindholm P, Peranen J, Saarma M, Tuominen RK: Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease. J Neurosci 2009, 29:9651-9659.
6. Lindholm P, Saarma M: Novel CDNF/MANF family of neurotrophic factors. Dev Neurobiol 2010, 70:360-371.
7. Palgi M, Lindstrom R, Peranen J, Piepponen TP, Saarma M, Heino TI: Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proc Natl Acad Sci U S A 2009, 106:2429-2434.
8. Parkash V, Lindholm P, Peranen J, Kalkkinen N, Oksanen E, Saarma M, Leppanen VM, Goldman A: The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel 2009, 22:233-241.
9. Hellman M, Arumae U, Yu LY, Lindholm P, Peranen J, Saarma M, Permi P: Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. J Biol Chem 2011, 286:2675-2680.
10. Airavaara M, Harvey BK, Voutilainen MH, Shen H, Chou J, Lindholm P, Lindahl M, Tuominen RK, Saarma M, Hoffer B, Wang Y: CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant 2012, 21:1213-1223.
11. Ren X, Zhang T, Gong X, Hu G, Ding W, Wang X: AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in a 6-hydroxydopamine induced parkinsonian rat model. Exp Neurol 2013, 248:148-156.
12. Back S, Peranen J, Galli E, Pulkkila P, Lonka-Nevalaita L, Tamminen T, Voutilainen MH, Raasmaja A, Saarma M, Mannisto PT, Tuominen RK: Gene therapy with AAV2-CDNF provides functional benefits in a rat model of Parkinson's disease. Brain Behav 2013, 3:75-88.
13. Voutilainen MH, Back S, Peranen J, Lindholm P, Raasmaja A, Mannisto PT, Saarma M, Tuominen RK: Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Exp Neurol 2011, 228:99-108.
14. Cheng L, Liu Y, Zhao H, Zhang W, Guo YJ, Nie L: Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats. Biochem Biophys Res Commun 2013, 440:330-335.
15. Cheng L, Zhao H, Zhang W, Liu B, Liu Y, Guo Y, Nie L: Overexpression of conserved dopamine neurotrophic factor (CDNF) in astrocytes alleviates endoplasmic reticulum stress-induced cell damage and inflammatory cytokine secretion. Biochem Biophys Res Commun 2013, 435:34-39.
16. Zhao H, Cheng L, Liu Y, Zhang W, Maharjan S, Cui Z, Wang X, Tang D, Nie L: Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of JNK signaling in lipopolysaccharide-induced microglia. J Mol Neurosci 2014, 52:186-192.
17. Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC: Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease. Neurosci Lett 1994, 172:151-154.
18. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T: Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett 1994, 180:147-150.
19. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T: Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 1994, 165:208-210.
20. Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M: Proteome analysis of human substantia nigra in Parkinson's disease. Proteomics 2004, 4:3943-3952.
21. Teismann P, Schulz JB: Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation. Cell Tissue Res 2004, 318:149-161.
22. Taylor JM, Main BS, Crack PJ: Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson's disease. Neurochem Int 2013, 62:803-819.
23. 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.
24. Bove J, Perier C: Neurotoxin-based models of Parkinson's disease. Neuroscience 2012, 211:51-76.
25. Jackson-Lewis V, Blesa J, Przedborski S: Animal models of Parkinson's disease. Parkinsonism Relat Disord 2012, 18(Suppl 1):S183-S185.
26. Decressac M, Mattsson B, Bjorklund A: Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson's disease. Exp Neurol 2012, 235:306-315.
27. Blandini F: Neural and immune mechanisms in the pathogenesis of Parkinson's disease. J Neuroimmune Pharmacol 2013, 8:189-201.
28. Sanchez-Iglesias S, Rey P, Mendez-Alvarez E, Labandeira-Garcia JL, Soto-Otero R: Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson's disease. Neurochem Res 2007, 32:99-105.
29. 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.
30. Chertoff M, Di Paolo N, Schoeneberg A, Depino A, Ferrari C, Wurst W, Pfizenmaier K, Eisel U, Pitossi F: Neuroprotective and neurodegenerative effects of the chronic expression of tumor necrosis factor alpha in the nigrostriatal dopaminergic circuit of adult mice. Exp Neurol 2011, 227:237-251.
31. Leal MC, Casabona JC, Puntel M, Pitossi FJ: Interleukin-1beta and tumor necrosis factor-alpha: reliable targets for protective therapies in Parkinson's disease? Front Cell Neurosci 2013, 7:53.
32. Song C, Zhang Y, Dong Y: Acute and subacute IL-1beta administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. J Neuroinflammation 2013, 10:59.
33. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999, 97:703-716.
34. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A: Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 2004, 478:359-378.
35. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Gotz M: Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A 2008, 105:3581-3586.
36. Nishiyama A: Polydendrocytes: NG2 cells with many roles in development and repair of the CNS. Neuroscientist 2007, 13:62-76.
37. Hill RA, Nishiyama A: NG2 cells (polydendrocytes): listeners to the neural network with diverse properties. Glia 2014, 62:1195-1210.
38. Belachew S, Chittajallu R, Aguirre AA, Yuan X, Kirby M, Anderson S, Gallo V: Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol 2003, 161:169-186.
39. Labombarda F, Meffre D, Delespierre B, Krivokapic-Blondiaux S, Chastre A, Thomas P, Pang Y, Lydon JP, Gonzalez SL, De Nicola AF, Schumacher M, Guennoun R: Membrane progesterone receptors localization in the mouse spinal cord. Neuroscience 2010, 166:94-106.
40. Tripathi RB, Rivers LE, Young KM, Jamen F, Richardson WD: NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease. J Neurosci 2010, 30:16383-16390.
41. Leoni G, Rattray M, Butt AM: NG2 cells differentiate into astrocytes in cerebellar slices. Mol Cell Neurosci 2009, 42:208-218.
42. Zhu X, Bergles DE, Nishiyama A: NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 2008, 135:145-157.
43. Kitamura Y, Inden M, Minamino H, Abe M, Takata K, Taniguchi T: The 6-hydroxydopamine-induced nigrostriatal neurodegeneration produces microglia-like NG2 glial cells in the rat substantia nigra. Glia 2010, 58:1686-1700.
44. Martinez-Fong D, Bannon MJ, Trudeau LE, Gonzalez-Barrios JA, Arango-Rodriguez ML, Hernandez-Chan NG, Reyes-Corona D, Armendariz-Borunda J, Navarro-Quiroga I: NTS-Polyplex: a potential nanocarrier for neurotrophic therapy of Parkinson's disease. Nanomedicine 2012, 8:1052-1069.
45. Martinez-Fong D, Navarro-Quiroga I: Synthesis of a non-viral vector for gene transfer via the high-affinity neurotensin receptor. Brain Res Brain Res Protoc 2000, 6:13-24.
46. Alvarez-Maya I, Navarro-Quiroga I, Meraz-Rios MA, Aceves J, Martinez-Fong D: In vivo gene transfer to dopamine neurons of rat substantia nigra via the high-affinity neurotensin receptor. Mol Med 2001, 7:186-192.
47. Arango-Rodriguez ML, Navarro-Quiroga I, Gonzalez-Barrios JA, Martinez-Arguelles DB, Bannon MJ, Kouri J, Forgez P, Rostene W, Garcia-Villegas R, Jimenez I, Martinez-Fong D: Biophysical characteristics of neurotensin polyplex for in vitro and in vivo gene transfection. Biochim Biophys Acta 2006, 1760:1009-1020.
48. Hernandez-Baltazar D, Martinez-Fong D, Trudeau LE: Optimizing NTS-polyplex as a tool for gene transfer to cultured dopamine neurons. PLoS One 2012, 7:e51341.
49. Gonzalez-Barrios JA, Lindahl M, Bannon MJ, Anaya-Martinez V, Flores G, Navarro-Quiroga I, Trudeau LE, Aceves J, Martinez-Arguelles DB, Garcia-Villegas R, Jimnez I, Segovia J, Martinz-Fong D: Neurotensin polyplex as an efficient carrier for delivering the human GDNF gene into nigral dopamine neurons of hemiparkinsonian rats. Mol Ther 2006, 14:857-865.
50. Hernandez ME, Rembao JD, Hernandez-Baltazar D, Castillo-Rodriguez RA, Tellez-Lopez VM, Flores-Martinez YM, Orozco-Barrios CE, Rubio HA, Sanchez-Garcia A, Ayala-Davila J, Arango-Rodriguez ML, Pavn L, Mejia-Castillo T, Forgez P, Martinez-Fong D: Safety of the intravenous administration of neurotensin-polyplex nanoparticles in BALB/c mice. Nanomedicine 2014, 10:745-754.
51. Hernandez-Baltazar D, Mendoza-Garrido ME, Martinez-Fong D: Activation of GSK-3beta and caspase-3 occurs in nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PLoS One 2013, 8:e70951.
52. Navarro-Quiroga I, Antonio Gonzalez-Barrios J, Barron-Moreno F, Gonzalez-Bernal V, Martinez-Arguelles DB, Martinez-Fong D: Improved neurotensin-vector-mediated gene transfer by the coupling of hemagglutinin HA2 fusogenic peptide and Vp1 SV40 nuclear localization signal. Brain Res Mol Brain Res 2002, 105:86-97.
53. Castillo-Rodrguez RA, Arango-Rodrguez ML, Escobedo L, Hernandez-Baltazar D, Gompel A, Forgez P, Martinez-Fong D: Suicide HSVtk gene delivery by neurotensin-polyplex nanoparticles via the bloodstream and GCV treatment specifically inhibit the growth of human MDA-MB-231 triple negative breast cancer tumors xenografted in athymic mice. PLoS ONE 2014, 13:e97151.
54. Zhang Y, Chen Q: Changes of matrilin forms during endochondral ossification. Molecular basis of oligomeric assembly. J Biol Chem 2000, 275:32628-32634.
55. Xiang QF, Zhang DM, Wang JN, Zhang HW, Zheng ZY, Yu DC, Li YJ, Xu J, Chen YJ, Shang CZ: Cabozantinib reverses multidrug resistance of human hepatoma HepG2/adr cells by modulating the function of P-glycoprotein. Liver Int 2014. (In Press).
56. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(Delta-Delta C(T)) Method. Methods 2001, 25:402-408.
57. Erickson MA, Banks WA: Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun 2011, 25:1637-1648.
58. Blanco-Alvarez VM, Lopez-Moreno P, Soto-Rodriguez G, Martinez-Fong D, Rubio H, Gonzalez-Barrios JA, Pina-Leyva C, Torres-Soto M, Gomez-Villalobos Mde J, Hernandez-Baltazar D, Brambila E, Eguibar JR, Ugarte A, Cebada J, Leon-Chavez BA: Subacute zinc administration and L-NAME caused an increase of NO, zinc, lipoperoxidation, and caspase-3 during a cerebral hypoxia-ischemia process in the rat. Oxid Med Cell Longev 2013, 2013:240560.
59. Zhu X, Hill RA, Nishiyama A: NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord. Neuron Glia Biol 2008, 4:19-26.
60. Franco Rodriguez NE, Duenas Jimenez JM, De la Torre VB, Lopez Ruiz JR, Hernandez Hernandez L, Duenas Jimenez SH: Tamoxifen favoured the rat sensorial cortex regeneration after a penetrating brain injury. Brain Res Bull 2013, 98:64-75.
61. Greenbaum D, Colangelo C, Williams K, Gerstein M: Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003, 4:117.
62. Maier T, Guell M, Serrano L: Correlation of mRNA and protein in complex biological samples. FEBS Lett 2009, 583:3966-3973.
63. Vogel C, Marcotte EM: Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012, 13:227-232.
64. Vogel C, Silva GM, Marcotte EM: Protein expression regulation under oxidative stress. Mol Cell Proteomics 2011, 10:M111 009217.
65. Fournier ML, Paulson A, Pavelka N, Mosley AL, Gaudenz K, Bradford WD, Glynn E, Li H, Sardiu ME, Fleharty B, Seidel C, Florens L, Washburn MP: Delayed correlation of mRNA and protein expression in rapamycin-treated cells and a role for Ggc1 in cellular sensitivity to rapamycin. Mol Cell Proteomics 2010, 9:271-284.
66. Sacchetti P, Brownschidle LA, Granneman JG, Bannon MJ: Characterization of the 5'-flanking region of the human dopamine transporter gene. Brain Res Mol Brain Res 1999, 74:167-174.
67. Hiromura M, Suizu F, Narita M, Kinowaki K, Noguchi M: Identification of nerve growth factor-responsive element of the TCL1 promoter as a novel negative regulatory element. J Biol Chem 2006, 281:27753-27764.
68. Iwawaki T, Kohno K, Kobayashi K: Identification of a potential nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells. Biochem Biophys Res Commun 2000, 274:590-595.
69. Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindgvist E, Larsson NG, Olson L, Bjorklund A, Ichinose H, Perlmann T: Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 2009, 29:15923-15932.
70. Zetterstrom RH, Williams R, Perlmann T, Olson L: Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 1996, 41:111-120.
71. Garcia-Yague AJ, Rada P, Rojo AI, Lastres-Becker I, Cuadrado A: Nuclear import and export signals control the subcellular localization of Nurr1 protein in response to oxidative stress. J Biol Chem 2013, 288:5506-5517.
72. Sawada H, Hishida R, Hirata Y, Ono K, Suzuki H, Muramatsu S, Nakano I, Nagatsu T, Sawada M: Activated microglia affect the nigro-striatal dopamine neurons differently in neonatal and aged mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurosci Res 2007, 85:1752-1761.
73. Kuno R, Yoshida Y, Nitta A, Nabeshima T, Wang J, Sonobe Y, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A: The role of TNF-alpha and its receptors in the production of NGF and GDNF by astrocytes. Brain Res 2006, 1116:12-18.
74. Figiel I: Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain. Acta Neurobiol Exp (Wars) 2008, 68:526-534.
75. Saha RN, Liu X, Pahan K: Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 2006, 1:212-222.
76. Jana M, Anderson JA, Saha RN, Liu X, Pahan K: Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes. Free Radic Biol Med 2005, 38:655-664.
77. Poli V: The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem 1998, 273:29279-29282.
78. Sticozzi C, Belmonte G, Meini A, Carbotti P, Grasso G, Palmi M: IL-1beta induces GFAP expression in vitro and in vivo and protects neurons from traumatic injury-associated apoptosis in rat brain striatum via NFkappaB/Ca(2)(+)-calmodulin/ERK mitogen-activated protein kinase signaling pathway. Neuroscience 2013, 252:367-383.
79. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S: The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011, 1813:878-888.
80. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW: Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994, 83:113-118.
81. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK: IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998, 101:311-320.
82. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A: IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 2003, 4:551-556.
83. Islam O, Gong X, Rose-John S, Heese K: Interleukin-6 and neural stem cells: more than gliogenesis. Mol Biol Cell 2009, 20:188-199.
84. Marz P, Cheng JG, Gadient RA, Patterson PH, Stoyan T, Otten U, Rose-John S: Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci U S A 1998, 95:3251-3256.
85. Marz P, Otten U, Rose-John S: Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. Eur J Neurosci 1999, 11:2995-3004.
86. Nguyen MD, Julien JP, Rivest S: Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 2002, 3:216-227.