Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Rolle von striatalen Tyrosinhydroxylase-positiven Neuronen bei L-DOPA-induzierten Dyskinesien der Maus
Autor:Keber, Ursula Johanna
Weitere Beteiligte: Depboylu, Candan (PD Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0630
DOI: https://doi.org/10.17192/z2014.0630
URN: urn:nbn:de:hebis:04-z2014-06309
DDC: Medizin
Titel (trans.):Striatal tyrosine hydroxylase-positive neurons are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice
Publikationsdatum:2014-10-01
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Tyrosine hydroxylase, FosB, Dopamin, aromatic acid decarboxylase, Neuronale Plastizität, Tyrosin, Aromatische Aminosäure-Decarboxylase, Cortex, L-Dopa, Corpus striatum, Dyskinesie, Nucleus accumbens, Serotonin, Serotonintransporter, dyskinesia, FosB, Substantia n, Parkinson-Krankheit, Tyrosinhydroxylase, absolute involuntary movements

Zusammenfassung:
Die Parkinson-Krankheit ist die zweithäufigste neurodegenerative Erkrankung weltweit. Der Goldstandard zur symptomatischen Behandlung ist der Wirkstoff L 3,4 Dihydroxyphenylalanin (L-DOPA), der im Verlauf jedoch bei vielen Patienten ausgeprägte motorische Nebenwirkungen in Form von abnormen unfreiwilligen Bewegungen, sogenannten L-DOPA-induzierten Dyskinesien (LID), hervorruft. Deren genaue Ätiopathogenese liegt bislang noch im Dunkeln. Das Ziel dieser Arbeit war es, die Expression Tyrosinhydroxylase(TH)-positiver und damit L-DOPA-produzierender Zellen im denervierten Corpus striatum (Striatum) als fundamentalen Faktor für die Entstehung und Ausprägung von LID aufzudecken. Hierzu wurden 6-Hydroxydopamin-lädierte Mäuse über 15 Tage mit L-DOPA behandelt, das Auftreten von LID wurde charakterisiert und mit der immunhistochemisch bestimmten Anzahl striataler TH-positiver Zellen korreliert. Bemerkenswerterweise entwickelten 70% der L-DOPA-behandelten Mäuse ausgeprägte LID, die mit einer deutlich gesteigerten Expression TH-positiver Neurone einhergingen und deren Ausprägung eng mit der Zellzahl korrelierte. Die Zunahme TH-positiver Neurone stand im Einklang mit einer gesteigerten Expression von ∆FosB, einem validen molekularen Marker für Dyskinesien. Zudem wiesen dyskinetische Tiere eine erhöhte serotonerge Innervation des Striatums auf – Fasern, die mit ihrer aromatischen Aminosäure-Decarboxylase eine Konversion von L-DOPA in Dopamin vollführen können. Es ist also davon auszugehen, dass die TH-positiven Zellen synergistisch mit serotonergen Terminalen Dopamin synthetisieren und damit erhöhte extrazelluläre Dopaminkonzentrationen begünstigen. Dieser ursprünglich kompensatorische Mechanismus als Antwort auf das striatale dopaminerge Defizit beim Morbus Parkinson scheint im Rahmen einer L-DOPA-Therapie über das Ziel hinaus zu schießen und resultiert in der Entwicklung von LID. Zentraler Entstehungsort ist hierbei das laterale, dem menschlichen Putamen entsprechende Striatum, wohingegen ein prodyskinetischer Effekt der TH-Zellen im Nucleus accumbens und im Cortex ausgeschlossen werden konnte. Die Erkenntnisse dieser Arbeit tragen grundlegend zu einem besseren Verständnis über die Ätiopathogenese von LID und die Funktionalität der weitgehend unerforschten TH positiven Neurone bei. Zukünftige Studien, die sich die TH-positiven Zellen für eine potentielle Parkinsontherapie zunutze machen wollen, sollten deren LID-provozierenden Effekt kritisch berücksichtigen. Auf der anderen Seite könnten diese Neurone langfristig einen hoffnungsvollen Ansatz für neue antidyskinetische Behandlungsstrategien liefern.

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