Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models
Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models
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DOI：
10.1002/mds.28558
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发表时间：
2021-04-04
影响因子：
8.6
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Ueda, Jun;Uemura, Norihito;Takahashi, Ryosuke
背景致病蛋白的细胞间传递在神经退行性疾病的临床病理进展中起着关键作用。以往的研究表明，这种摄取和释放过程受神经元活动的调节。目的本研究的目的是检查perampanel，一种抗癫痫药物，方法用α-突触核蛋白预形成的原纤维转导小鼠原代海马神经元，以检查perampanel对α-突触核蛋白发育的影响。突触核蛋白病理学及其作用机制。使用α-突触核蛋白预制原纤维注射小鼠模型验证perampanel口服给药对体内α-突触核蛋白病理学的影响。结果Perampanel抑制了用α-突触核蛋白预制原纤维转导的小鼠海马神经元中α-突触核蛋白病理学的发展。有趣的是，perampanel通过以神经元活性依赖性方式抑制巨胞饮作用，阻断神经元对α-突触核蛋白预制原纤维的摄取。我们证实口服perampanel可改善接种α-突触核蛋白预形成纤维的野生型小鼠中α-突触核蛋白病理学的发展。结论调节神经元活性可能是帕金森病的一个有前途的治疗靶点，perampanel可能是帕金森病的一种新型疾病改善药物。(c)2021国际帕金森和运动障碍协会
Background The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.Objective The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on alpha-synuclein transmission in cultured cells and mouse models of Parkinson's disease.Methods Mouse primary hippocampal neurons were transduced with alpha-synuclein preformed fibrils to examine the effect of perampanel on the development of alpha-synuclein pathology and its mechanisms of action. An alpha-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the alpha-synuclein pathology in vivo.Results Perampanel inhibited the development of alpha-synuclein pathology in mouse hippocampal neurons transduced with alpha-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of alpha-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of alpha-synuclein pathology in wild-type mice inoculated with alpha-synuclein preformed fibrils.Conclusion Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease-modifying drug for Parkinson's disease. (c) 2021 International Parkinson and Movement Disorder Society