Date Published: June 10, 2019
Publisher: Public Library of Science
Author(s): Christine Kaindlstorfer, Nadia Stefanova, Joanna Garcia, Florian Krismer, Máté Döbrössy, Georg Göbel, Kurt Jellinger, Roberta Granata, Gregor Karl Wenning, David I. Finkelstein.
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.
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). 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.
Neurotoxic lesion models are valuable to study motor symptoms and investigate neuroanatomical correlations and therapeutic approaches in neurodegenerative diseases including multiple system atrophy . Multiple system atrophy (MSA) is an adult onset, rapidly progressive neurodegenerative disease characterized by progressive autonomic failure in combination with parkinsonism and/or cerebellar symptoms and pyramidal features . Disease onset is in the sixth decade, both sexes are equally affected, and mean survival is estimated to be 6–9 years [1,3–6]. 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 . 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) [8–10]. However, both systems are usually affected within one individual. Histologically, both motor variants of MSA feature a common and disease-specific cellular pathology of α-synuclein (α-SYN) immunoreactive aggregates in oligodendrocytes, which are referred to as (oligodendro-) glial cytoplasmic inclusion bodies .
Previously we have shown that partial dopaminergic denervation and excitotoxic lesions of the lateral motor striatum cause abnormalities of drug-induced circling and spontaneous complex motor deficits in a double lesion rat model of early stage MSA-P/SND . We here demonstrate that L-dopa response failure is similar in the mild and advanced stage MSA-P/SND model. Since the restricted neuropathology achieved by this partial lesion paradigm more closely replicates human MSA-P, and because early treatment intervention is essential in a rapidly progressive neurodegenerative disease like MSA, the mild MSA-P/SND model represents the more appropriate testbed for studying restoration of striatal circuitry using cell grafts.
We here characterize for the first time L-dopa response patterns in a partial double-lesion rat model of early stage MSA-P/SND with limited dopaminergic nigrostriatal denervation and striatal volume loss. Our mild MSA-P/SND double-lesion model provides a highly suitable testbed for cell-based restoration of striatal circuitry and reversal of L-dopa response failure.