Format

Send to

Choose Destination
PLoS One. 2019 Jun 10;14(6):e0218130. doi: 10.1371/journal.pone.0218130. eCollection 2019.

L-dopa response pattern in a rat model of mild striatonigral degeneration.

Author information

1
Division of Neurobiology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
2
University Medical Centre Freiburg, Department of Neurosurgery, Freiburg, Germany.
3
Medical University Innsbruck, Department of Medical Statistics, Informatics and Health Economics, Innsbruck, Austria.
4
Institute of Clinical Neurobiology, Vienna, Austria.

Abstract

BACKGROUND:

Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined striatonigral degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure.

METHODS AND RESULTS:

Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p<0.001). Response to L-dopa treatment declined in both MSA-P/SND groups reflecting striatal damage of lateral motor areas in contrast to the 6-OHDA only lesioned animals (p<0.01). The remaining striatal volume correlated strongly with contralateral apomorphine induced rotation behaviour and contralateral paw use during L-dopa treatment in cylinder and stepping test (p<0.001).

CONCLUSION:

Our novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.

Conflict of interest statement

The authors have declared that no competing interests exist.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center