Publikationsserver der Universitätsbibliothek Marburg

Titel:Effekte einer Langzeit-Therapie mit Pramipexol oder Levodopa auf die [123I]FP-CIT SPECT in einem Mausmodell der Parkinson-Krankheit
Autor:Maurer, Lukas
Weitere Beteiligte: Höglinger, Günter (Prof. Dr. med.)
Veröffentlicht:2015
URI:https://archiv.ub.uni-marburg.de/diss/z2015/0145
DOI: https://doi.org/10.17192/z2015.0145
URN: urn:nbn:de:hebis:04-z2015-01453
DDC:610 Medizin
Titel (trans.):Effect of long-term treatment with pramipexole or levodopa on presynaptic markers assessed by longitudinal [123I]FP-CIT SPECT and histochemistry
Publikationsdatum:2015-02-26
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Dopamine Agonist, SPECT, Neurodegeneration, Dopaminagonist, Pramipexol, Parkinson-Krankheit, Neurodegeneration, L-Dopa, Dopamine, SPECT, Neuroregeneration, Parkinson´s disease, Dopamin

Zusammenfassung:
Die zuvor durchgeführte klinische Studie CALM-PD (ParkinsonStudyGroup, 2002) untersuchte den Effekt einer Langzeittherapie mit Levodopa oder Pramipexol auf das Fortschreiten der Parkinson-Krankheit mittels SPECT unter Verwendung des Dopamintransporter-Liganden [123I]β-CIT als Surrogat-Marker. Die [123I]β-CIT Bindung fiel in den Patienten, die Levodopa erhalten hatten, auf ein signifikant niedrigeres Niveau ab, als bei den Patienten, die Pramipexol erhalten hatten. Allerdings wurde dieses Ergebnis unterschiedlich interpretiert, zum einen als Ausdruck Levodopa-induzierter Neurotoxizität, zum anderen als Pramipexol-induzierte Neuroprotektion / -regeneration oder auch als lediglich medikamentös-induzierte Veränderung der Dopamintransporter-Verfügbarkeit. Um diese Fragestellung experimentell zu untersuchen, induzierten wir in Mäusen eine subtotale, bilaterale Läsion der Substantia nigra durch Injektion des Neurotoxins 6-Hydroxydopamin. Vier Wochen danach wurden die Mäuse über einen Zeitraum von 20 Wochen oral mit Levodopa (100mg/kg/Tag), Pramipexol (3mg/kg/Tag) oder lediglich Wasser (Placebo) behandelt. Die Integrität der nigrostriatalen Projektion wurde in vivo wiederholt mittels [123I]FP-CIT SPECT gemessen, sowie nach Tötung der Tiere durch immunhistologische Untersuchung des Dopamintransporter und der Dopamin-synthetisierenden Tyrosinehydroxylase. In scheinlädierten Tieren zeigte sich, dass Levodopa ebenso wie Pramipexol sowohl die striatale FP-CIT Bindung (LD: -21%; PPX: -14%), als auch die TH-Immunreaktivität (LD: -42%, PPX: -45%) signifikant senkten. Gleichzeitig wurde die DAT-Immunreaktivität im Vergleich zu den Kontrolltieren ohne Dopamin-Therapie signifikant erhöht (LD: +42%; PPX +33%). In operierten Tieren mit 6-OHDA-Läsion hingegen hatten weder Levodopa noch Pramipexol einen signifikanten Einfluss auf das stabil reduzierte Niveau der FP-CIT SPECT-Bindung (LD: -66%; PPX: -66%; Placebo: -66%), die striatale TH-Immunreaktivität (LD: -70%, PPX: -72%; Placebo: -77%), die striatale DAT-Immunreaktivität (LD: -70%, PPX: -75%; Placebo: -75%) oder die Anzahl TH-positiver Zellen in der Substantia nigra (LD: -88%, PPX: -88%; Placebo: -86%) im Vergleich zu den Tieren ohne Dopamin-Therapie. Zusammenfassend zeigte sich, dass eine chronische dopaminerge Stimulation mit Levodopa oder Pramipexol ähnliche präsynaptische Anpassungsphänomene in gesunden Mäusen verursacht, allerdings keine erkennbaren Veränderungen in Mäusen mit ausgeprägter Läsion der nigrostriatalen dopaminergen Projektion. Die hier erzielten Ergebnisse ermöglichen eine verlässlichere Interpretation klinischer Studien, die Verfahren zur Dopamintransporter-Bildgebung als Surrogat-Parameter verwenden.

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