Dokument

Zusammenfassung:
Die Aktivierung der kalziumabhängigen Kaliumkanäle mit kleiner Leitfähigkeit (KCNN/SK/KCa2) ist ein vielversprechender therapeutischer Ansatz für die Behandlung von neurologischen Erkrankungen wie Schlaganfall, amyotrophe Lateralsklerose (ALS), Ataxie und Schizophrenie. In dieser Studie wurde das therapeutische Potential der SK-Kanalaktivierung in einem Rotenon-basierten Parkinson-in-vitro-Modell untersucht. Als Zellmodell wurden über 6 Tage differenzierte dopaminerge Neuronen aus einer immortalisierten humanen Zelllinie (LUHMES-Zellen) verwendet. Die konzentrationsabhängige Behandlung mit dem Komplex I-Inhibitor Rotenon (0,1-2,0 μM) zerstörte das dendritische Netzwerk der differenzierten dopaminergen Neuronen und führte zum Zelltod. Quantitative RT-PCR und Western Blot Analyse zeigen, dass die differenzierten dopaminergen Neurone wenig SK2-Kanäle und in hohem Maß SK1 und SK3 Kanäle exprimieren. Proteinuntersuchungen subzellulärer Fraktionen wiesen die Lokalisierung des SK2-Kanal-Subtyps in den Mitochondrien nach. Der positive SK-Kanalmodulator NS309 reduzierte das mitochondriale Membranpotential, während gleichzeitig das dendritische Netzwerk, die Lebensfähigkeit und die ATP-Spiegel der Zellen nach der Gabe von Rotenon erhalten blieben. Insgesamt zeigen die dargestellten Ergebnisse, dass die Aktivierung von SK-Kanälen protektive Effekte in menschlichen dopaminergen Neuronen bewirken, wahrscheinlich über die Aktivierung des mitochondrialen Membranpotentials durch SK-Kanäle. Somit kann die Aktivierung der SK-Kanäle ein vielversprechender therapeutischer Ansatz zur Behandlung von neurodegenerativen Erkrankungen wie der Parkinsonschen Krankheit sein, bei der dopaminerger Zellverlust mit dem Fortschreiten der Krankheit assoziiert wird.

Bibliographie / References

1. SCHAPIRA, A H: Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal. In: Movement disorders : official journal of the Movement Disorder Society Bd. 9 (1994), Nr. 2, S. 125–138
2. FALKENBURGER, B H ; SCHULZ, J B: Limitations of cellular models in Parkinson's disease research. In: Journal of neural transmission. Supplementum (2006), Nr. 70, S. 261–268
3. WOOD, P G: The spontaneous activation of a potassium channel during the preparation of resealed human erythrocyte ghosts. In: Biochimica et biophysica acta Bd. 774 (1984), Nr. 1, S. 103–109
4. TEIXEIRA, J R ; LAPA, A J ; SOUCCAR, C ; VALLE, J R: Timbós: ichthyotoxic plants used by Brazilian Indians. In: Journal of ethnopharmacology Bd. 10 (1984), Nr. 3, S. 311–318
5. HÖGLINGER, GÜNTER U ; FÉGER, JEAN ; PRIGENT, ANNICK ; MICHEL, PATRICK P ; PARAIN, KARINE ; CHAMPY, PIERRE ; RUBERG, MERLE ; OERTEL, WOLFGANG H ; HIRSCH, ETIENNE C: Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. In: Journal of neurochemistry Bd. 84 (2003), Nr. 3, S. 491–502
6. KIS, BELA ; RAJAPAKSE, NISHADI C ; SNIPES, JAMES A ; NAGY, KRISZTINA ; HORIGUCHI, TAKASHI ; BUSIJA, DAVID W: Diazoxide induces delayed pre- conditioning in cultured rat cortical neurons. In: Journal of neurochemistry Bd. 87 (2003), Nr. 4, S. 969–980
7. MEDANA, I M ; ESIRI, M M: Axonal damage: a key predictor of outcome in human CNS diseases. In: Brain : a journal of neurology Bd. 126 (2003), Nr. Pt 3, S. 515–530
8. LAPOINTE, NICOLAS ; ST-HILAIRE, MICHEL ; MARTINOLI, MARIA-GRAZIA ; BLANCHET, JULIE ; GOULD, PETER ; ROUILLARD, CLAUDE ; CICCHETTI, FRANCESCA: Rotenone induces non-specific central nervous system and systemic toxicity. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Bd. 18 (2004), Nr. 6, S. 717–719
9. FOUNTAINE, TIMOTHY M ; VENDA, LARA LOURENCO ; WARRICK, NICHOLAS ; CHRISTIAN, HELEN C ; BRUNDIN, PATRIK ; CHANNON, KEITH M ; WADE-MARTINS, RICHARD: The effect of alpha-synuclein knockdown on MPP+ toxicity in models of human neurons. In: The European journal of neuroscience Bd. 28 (2008), Nr. 12, S. 2459–2473
10. XIONG, NIAN ; LONG, XI ; XIONG, JING ; JIA, MIN ; CHEN, CHUNNUAN ; HUANG, JINSHA ; GHOORAH, DEVINA ; KONG, XIANGQUAN ; LIN, ZHICHENG ; U. A.: Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson's disease models. In: Critical reviews in toxicology Bd. 42 (2012), Nr. 7, S. 613–632
11. FABER, E S LOUISE ; SAH, PANKAJ: Functions of SK channels in central neurons. In: Clinical and experimental pharmacology & physiology Bd. 34 (2007), Nr. 10, S. 1077–1083
12. MOOTHA, VAMSI K ; BUNKENBORG, JAKOB ; OLSEN, JESPER V ; HJERRILD, MAJBRIT ; WISNIEWSKI, JACEK R ; STAHL, ERICH ; BOLOURI, MARJAN S ; RAY, HETA N ; SIHAG, SMITA ; U. A.: Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. In: Cell Bd. 115 (2003), Nr. 5, S. 629–640
13. FREESTONE, PETER S ; CHUNG, KENNY K H ; GUATTEO, EZIA ; MERCURI, NICOLA B ; NICHOLSON, LOUISE F B ; LIPSKI, JANUSZ: Acute action of rotenone on nigral dopaminergic neurons--involvement of reactive oxygen species and disruption of Ca2+ homeostasis. In: The European journal of neuroscience Bd. 30 (2009), Nr. 10, S. 1849–1859
14. HOULDEN, HENRY ; SINGLETON, ANDREW B: The genetics and neuropathology of Parkinson's disease. In: Acta neuropathologica Bd. 124 (2012), Nr. 3, S. 325–338
15. JØRGENSEN, SUSANNE ; DYHRING, TINO ; BROWN, DAVID T ; STRØBAEK, DORTE ; CHRISTOPHERSEN, PALLE ; DEMNITZ, JOACHIM: A high-throughput screening campaign for detection of ca(2+)-activated k(+) channel activators and inhibitors using a fluorometric imaging plate reader-based tl(+)-influx assay. In: Assay and drug development technologies Bd. 11 (2013), Nr. 3, S. 163– 172
16. WOLFART, J ; NEUHOFF, H ; FRANZ, O ; ROEPER, J: Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. In: The Journal of neuroscience : the official journal of the Society for Neuroscience Bd. 21 (2001), Nr. 10, S. 3443–3456
17. SHIMOHAMA, SHUN ; SAWADA, HIDEYUKI ; KITAMURA, YOSHIHISA ; TANIGUCHI, TAKASHI: Disease model: Parkinson's disease. In: Trends in molecular medicine Bd. 9 (2003), Nr. 8, S. 360–365
18. dopamine homeostasis in a new human mesencephalic cell line. In: The Journal of biological chemistry Bd. 277 (2002), Nr. 41, S. 38884–38894
19. SHEPARD, P D ; BUNNEY, B S: Effects of apamin on the discharge properties of putative dopamine-containing neurons in vitro. In: Brain research Bd. 463 (1988), Nr. 2, S. 380–384
20. OLANOW, C W ; TATTON, W G: Etiology and pathogenesis of Parkinson's disease. In: Annual review of neuroscience Bd. 22 (1999), S. 123–144
21. PLUMMER, HOWARD K ; YU, QIANG ; CAKIR, YAVUZ ; SCHULLER, HILDEGARD M: Expression of inwardly rectifying potassium channels (GIRKs) and beta- adrenergic regulation of breast cancer cell lines. In: BMC cancer Bd. 4 (2004), S. 93
22. GRAFF, L ; CASTROP, F ; BAUER, M ; HÖFLER, H ; GRATZL, M: Expression of vesicular monoamine transporters, synaptosomal-associated protein 25 and syntaxin1: a signature of human small cell lung carcinoma. In: Cancer research Bd. 61 (2001), Nr. 5, S. 2138–2144
23. LOHMANN, K ; BROCKMANN, K: [Genetics of movement disorders]. In: Der Nervenarzt Bd. 84 (2013), Nr. 2, S. 143–150
24. WEI, AGUAN D ; GUTMAN, GEORGE A ; ALDRICH, RICHARD ; CHANDY, K GEORGE ; GRISSMER, STEPHAN ; WULFF, HEIKE: International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. In: Pharmacological reviews Bd. 57 (2005), Nr. 4, S. 463–472
25. MAREY-SEMPER, I ; GELMAN, M ; LÉVI-STRAUSS, M: A selective toxicity toward cultured mesencephalic dopaminergic neurons is induced by the synergistic effects of energetic metabolism impairment and NMDA receptor activation. In: The Journal of neuroscience : the official journal of the Society for Neuroscience Bd. 15 (1995), Nr. 9, S. 5912–5918
26. PEROCCHI, FABIANA ; GOHIL, VISHAL M ; GIRGIS, HANY S ; BAO, X ROBERT ; MCCOMBS, JANET E ; PALMER, AMY E ; MOOTHA, VAMSI K: MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. In: Nature Bd. 467 (2010), Nr. 7313, S. 291–296
27. ORTH, MICHAEL ; TABRIZI, SARAH J: Models of Parkinson's disease. In: Movement disorders : official journal of the Movement Disorder Society Bd. 18 (2003), Nr. 7, S. 729–737 PAN-MONTOJO, FRANCISCO J ; FUNK, RICHARD H W: Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system. In: Journal of visualized experiments : JoVE (2010), Nr. 44
28. PEDARZANI, P ; STOCKER, M: Molecular and cellular basis of small--and intermediate-conductance, calcium-activated potassium channel function in the brain. In: Cellular and molecular life sciences : CMLS Bd. 65 (2008), Nr. 20, S. 3196–3217
29. JELLINGER, K A: Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. In: Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid Bd. 14 (1991), Nr. 3, S. 153–197
30. LOTHARIUS, JULIE ; FALSIG, JEPPE ; VAN BEEK, JOHAN ; PAYNE, SARAH ; DRINGEN, RALF ; BRUNDIN, PATRIK ; LEIST, MARCEL: Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine- dependent oxidative stress is dependent on the mixed-lineage kinase pathway. In: The Journal of neuroscience : the official journal of the Society for Neuroscience Bd. 25 (2005), Nr. 27, S. 6329–6342
31. SCHILDKNECHT, STEFAN ; PÖLTL, DOMINIK ; NAGEL, DANIEL M ; MATT, FLORIAN ; SCHOLZ, DIANA ; LOTHARIUS, JULIE ; SCHMIEG, NATHALIE ; SALVO-VARGAS, ALBERTO ; LEIST, MARCEL: Requirement of a dopaminergic neuronal phenotype for toxicity of low concentrations of 1-methyl-4-phenylpyridinium to human cells. In: Toxicology and applied pharmacology Bd. 241 (2009), Nr. 1, S. 23–35
32. XIE, HONG-RONG ; HU, LIN-SEN ; LI, GUO-YI: SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson's disease. In: Chinese medical journal Bd. 123 (2010), Nr. 8, S. 1086–1092
33. KÖHLER, M ; HIRSCHBERG, B ; BOND, C T ; KINZIE, J M ; MARRION, N V ; MAYLIE, J ; ADELMAN, J P: Small-conductance, calcium-activated potassium channels from mammalian brain. In: Science (New York, N.Y.) Bd. 273 (1996), Nr. 5282, S. 1709–1714
34. TRZASKA, KATARZYNA A ; KUZHIKANDATHIL, ELDO V ; RAMESHWAR, PRANELA: Specification of a dopaminergic phenotype from adult human mesenchymal Literaturverzeichnis 95
35. SHERER, TODD B ; KIM, JIN HO ; BETARBET, RANJITA ; GREENAMYRE, J TIMOTHY: Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. In: Experimental neurology Bd. 179 (2003), Nr. 1, S. 9–16
36. JI, HUIFANG ; HOUGAARD, CHARLOTTE ; HERRIK, KJARTAN FRISCH ; STRØBAEK, DORTE ; CHRISTOPHERSEN, PALLE ; SHEPARD, PAUL D: Tuning the excitability of midbrain dopamine neurons by modulating the Ca2+ sensitivity of SK channels. In: The European journal of neuroscience Bd. 29 (2009), Nr. 9, S. 1883–1895
37. PUSCHMANN, ANDREAS: Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations. In: Parkinsonism & related disorders Bd. 19 (2013), Nr. 4, S. 407–415
38. ZENG, XIANMIN ; CAI, JINGLI ; CHEN, JIA ; LUO, YONGQUAN ; YOU, ZHI-BING ; FOTTER, ERIN ; WANG, YUN ; HARVEY, BRANDON ; MIURA, TAKUMI ; U. A.: Dopaminergic differentiation of human embryonic stem cells. In: Stem cells (Dayton, Ohio) Bd. 22 (2004), Nr. 6, S. 925–940
39. CAROLINE ; SMITH, RUBEN ; BRUNDIN, PATRIK: Tyrosine hydroxylase expression is unstable in a human immortalized mesencephalic cell line-- studies in vitro and after intracerebral grafting in vivo. In: Molecular and cellular neurosciences Bd. 34 (2007), Nr. 3, S. 390–399
40. SCHOLZ, DIANA ; PÖLTL, DOMINIK ; GENEWSKY, ANDREAS ; WENG, MATTHIAS ; WALDMANN, TANJA ; SCHILDKNECHT, STEFAN ; LEIST, MARCEL: Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. In: Journal of neurochemistry Bd. 119 (2011), Nr. 5, S. 957–971
41. FANG, NIANBAI ; CASIDA, JOHN E: Novel Bioactive Cubé Insecticide Constituents: Isolation and Preparation of 13-homo-13-Oxa-6a,12a-dehydrorotenoids. In: The Journal of organic chemistry Bd. 62 (1997), Nr. 2, S. 350–353
42. TAUPIN, PHILIPPE: BrdU immunohistochemistry for studying adult neurogenesis: paradigms, pitfalls, limitations, and validation. In: Brain research reviews Bd. 53 (2007), Nr. 1, S. 198–214
43. FUNKE, CLAUDIA ; SCHNEIDER, SUSANNE A ; BERG, DANIELA ; KELL, DOUGLAS B: Genetics and iron in the systems biology of Parkinson's disease and some related disorders. In: Neurochemistry international Bd. 62 (2013), Nr. 5, S. 637–652
44. LOTHARIUS, JULIE ; BRUNDIN, PATRIK: Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. In: Nature reviews. Neuroscience Bd. 3 (2002), Nr. 12, S. 932–942
45. STOCKER, MARTIN: Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. In: Nature reviews. Neuroscience Bd. 5 (2004), Nr. 10, S. 758–770
46. MAXWELL, SARAH L ; LI, MENG: Midbrain dopaminergic development in vivo and in vitro from embryonic stem cells. In: Journal of anatomy Bd. 207 (2005), Nr. 3, S. 209–218
47. HOUGAARD, C ; ERIKSEN, B L ; JØRGENSEN, S ; JOHANSEN, T H ; DYHRING, T ; MADSEN, L S ; STRØBAEK, D ; CHRISTOPHERSEN, P: Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+- activated K+ channels. In: British journal of pharmacology Bd. 151 (2007), Nr. 5, S. 655–665
48. TANNER, CAROLINE M ; KAMEL, FREYA ; ROSS, G WEBSTER ; HOPPIN, JANE A ; GOLDMAN, SAMUEL M ; KORELL, MONICA ; MARRAS, CONNIE ; BHUDHIKANOK, GRACE S ; KASTEN, MEIKE ; U. A.: Rotenone, paraquat, and Parkinson's disease. In: Environmental health perspectives Bd. 119 (2011), Nr. 6, S. 866–872
49. PERRY, SETH W ; NORMAN, JOHN P ; BARBIERI, JUSTIN ; BROWN, EDWARD B ; GELBARD, HARRIS A: Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. In: BioTechniques Bd. 50 (2011), Nr. 2, S. 98–115
50. STRØBAEK, DORTE ; TEUBER, LENE ; JØRGENSEN, TINO D ; AHRING, PHILIP K ; KJAER, KATRINE ; HANSEN, RIE S ; OLESEN, SØREN PETER ; CHRISTOPHERSEN, PALLE ; SKAANING-JENSEN, BO: Activation of human IK and SK Ca2+ - activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione 3- oxime). In: Biochimica et biophysica acta Bd. 1665 (2004), Nr. 1-2, S. 1–5
51. POOL, MADELINE ; THIEMANN, JOACHIM ; BAR-OR, AMIT ; FOURNIER, ALYSON E: NeuriteTracer: a novel ImageJ plugin for automated quantification of neurite outgrowth. In: Journal of neuroscience methods Bd. 168 (2008), Nr. 1, S. 134–139
52. LEE, JONG-MIN ; ANDERSON, PETER C ; PADGITT, JANETTE K ; HANSON, JANEAN M ; WATERS, CHRISTOPHER M ; JOHNSON, JEFFREY A: Nrf2, not the estrogen receptor, mediates catechol estrogen-induced activation of the antioxidant responsive element. In: Biochimica et biophysica acta Bd. 1629 (2003), Nr. 1-3, S. 92–101
53. SHASTRY, B S: Parkinson disease: etiology, pathogenesis and future of gene therapy. In: Neuroscience research Bd. 41 (2001), Nr. 1, S. 5–12
54. SCHÜLE, BIRGITT ; PERA, RENEE A REIJO ; LANGSTON, J WILLIAM: Can cellular models revolutionize drug discovery in Parkinson's disease? In: Biochimica Literaturverzeichnis 94
55. SIMEONE, ANTONIO: Genetic control of dopaminergic neuron differentiation. In: Trends in neurosciences Bd. 28 (2005), Nr. 2, S. 62–5– discussion 65–6

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