Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models

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 α-synuclein transmission in cultured cells and mouse models of Parkinson's disease. METHODS: Mouse primary hippocampal neurons were transduced with α-synuclein preformed fibrils to examine the effect of perampanel on the development of α-synuclein pathology and its mechanisms of action. An α-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the α-synuclein pathology in vivo. RESULTS: Perampanel inhibited the development of α-synuclein pathology in mouse hippocampal neurons transduced with α-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α-synuclein pathology in wild-type mice inoculated with α-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. © 2021 International Parkinson and Movement Disorder Society.