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 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

Automated summary

This study found that the antiepileptic drug perampanel can inhibit the transmission of alpha-synuclein in neurons by blocking macropinocytosis dependent on neuronal activity, thus potentially serving as a novel disease-modifying drug for Parkinson's disease.