Die Rolle von striatalen Tyrosinhydroxylase-positiven Neuronen bei L-DOPA-induzierten Dyskinesien der Maus
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Philipps-Universität Marburg
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Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. The gold standard of medication is the dopamine precursor L 3,4 Dihydroxyphenylalanin (L-DOPA). However, long-term treatment is complicated by the induction of abnormal involuntary movements, so called L-DOPA-induced dyskinesias (LID), in the vast majority of patients. So far, little is known about the underlying mechanisms of LID pathogenesis. The aim of this thesis was to reveal a factor, which may be critically involved in the induction and severity of LID: the expression of tyrosine hydroxylase(TH)-positive neurons, which are capable of producing L-DOPA in the denervated corpus striatum (striatum).
To address this issue, a daily L-DOPA dose was administered to 6-hydroxydopamine lesioned mice over the course of 15 days. The occurrence and severity of LID was determined and correlated with the number of striatal TH-positive cells. Remarkably, 70% of the animals developed severe LID, which was strongly associated with an increased expression of TH-positive neurons. According to these findings, the activity of ∆FosB as a valid molecular marker for LID was upregulated analogously. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the conversion of L-DOPA to dopamine via the aromatic amino-acid decarboxylating enzyme. These lines of evidence support the assumption that TH-positive cells and serotonergic terminals synergistically synthesize dopamine and subsequently contribute to supraphysiological dopamine concentrations. This mechanism that initially compensates the striatal dopamine deficit in PD may be overregulated during L-DOPA treatment and hence lead to the generation of LID. The pivotal region of origin was the lateral striatum corresponding to the human putamen whereas TH-positive cells in nucleus accumbens and cortex did not show any prodyskinetic effect.
Overall, the findings of this study provide compelling information for a better understanding of LID pathogenesis and the functionality of enigmatic TH-positive neurons. Future studies, which favor TH-positive neurons as a potential cell-based therapy for PD, should critically consider its LID triggering effect. On the other hand, TH-positive neurons could become the basis of a promising new approach for antidyskinetic treatment strategies.
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Dates
Created: 2014Issued: 2014-10-01Updated: 2014-10-01
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Aromatische Aminosäure-Decarboxylaseabsolute involuntary movementsaromatic acid decarboxylaseFosBTyrosinhydroxylaseTyrosine hydroxylaseFosBdyskinesiaCortexSerotonintransporter
DFG-subjects
DopaminNeuronale PlastizitätTyrosinL-DopaCorpus striatumDyskinesieNucleus accumbensSerotoninSubstantia nParkinson-Krankheit
DDC-Numbers
610
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Keber, Ursula Johanna (105889286X): Die Rolle von striatalen Tyrosinhydroxylase-positiven Neuronen bei L-DOPA-induzierten Dyskinesien der Maus. : Philipps-Universität Marburg 2014-10-01. DOI: https://doi.org/10.17192/z2014.0630.
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This item has been published with the following license: In Copyright