Division of Neurobiology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
University Medical Centre Freiburg, Department of Neurosurgery, Freiburg, Germany.
PLoS One. 2019 Jun 10;14(6):e0218130. doi: 10.1371/journal.pone.0218130. eCollection 2019.
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.
对多巴胺能治疗无反应是多系统萎缩（MSA）诊断的一个关键特征，也是由于纹状体黑质变性（SND）导致的 MSA 患者治疗的主要未满足需求。转基因α-突触核蛋白动物模型无法重现这种缺乏左旋多巴反应性的现象。为了在临床前研究包括纹状体细胞移植在内的干预措施，需要具有 SND 的模型。之前的大多数研究都集中在广泛的黑质和纹状体损伤，这些损伤对应于晚期 MSA-P/SND。本研究的目的是复制伴有左旋多巴失败的轻度 MSA-P/SND。
研究了两种不同的纹状体喹啉酸（QA）损伤，分别复制了轻度和重度 MSA-P/SND，与 6-OHDA 损伤动物进行了比较。在初始的 6-OHDA 损伤后，在圆柱体和踏步试验中，多巴胺能刺激后的运动性能有显著改善（p<0.001）。在两种 MSA-P/SND 组中，左旋多巴治疗的反应都下降了，反映了与仅接受 6-OHDA 损伤的动物相比，外侧运动区的纹状体损伤（p<0.01）。剩余的纹状体体积与对侧阿扑吗啡诱导的旋转行为以及在圆柱体和踏步试验中左旋多巴治疗时的对侧爪使用强烈相关（p<0.001）。
我们的新左旋多巴反应数据表明，通过限制外侧纹状体损伤与多巴胺能神经支配丧失相结合，可以诱导左旋多巴失败。我们提出，这种连续的纹状体双重损伤模型复制了 MSA-P/SND 的轻度阶段，适合解决旨在恢复多巴胺能反应性的神经再生治疗。
