Abstract
BackgroundUnresponsiveness 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 resultsTwo 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).ConclusionOur 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.
Highlights
Neurotoxic lesion models are valuable to study motor symptoms and investigate neuroanatomical correlations and therapeutic approaches in neurodegenerative diseases including multiple system atrophy [1]
We propose that this sequential striatal double-lesion model replicates a mild stage of Multiple system atrophy (MSA)-P/striatonigral degeneration (SND) and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness
According to the second consensus criteria in 2008, MSA patients can be categorized into the Parkinson (MSA-P) or cerebellar (MSA-C) clinical variants depending on the predominant motor presentation of either parkinsonism or cerebellar features [7]
Summary
Neurotoxic lesion models are valuable to study motor symptoms and investigate neuroanatomical correlations and therapeutic approaches in neurodegenerative diseases including multiple system atrophy [1]. According to the second consensus criteria in 2008, MSA patients can be categorized into the Parkinson (MSA-P) or cerebellar (MSA-C) clinical variants depending on the predominant motor presentation of either parkinsonism or cerebellar features [7] Both variants of MSA are neuropathologically characterized by neuronal loss in multiple brain regions including the autonomic, striatonigral and olivopontocerebellar systems. The degeneration of dopaminergic neurons in the substantia nigra and the medium sized spiny projection neurons of the striatum is predominant in MSA-P and is referred to as striatonigral degeneration (SND), while neurodegeneration in MSA-C is most prominently observed in the olivopontocerebellar system resulting in olivopontocerebellar atrophy (OPCA) [8,9,10] Both systems are usually affected within one individual. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure
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