Objective: To examine the effect of perampanel, an antiepileptic drug, on α-synuclein transmission in cultured cells and mouse models of Parkinson’s disease.

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.

Method: 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 fibrils-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: Targeting neuronal activity with perampanel could represent a new therapeutic strategy for Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/perampanel-inhibits-%ce%b1-synuclein-transmission-in-parkinsons-disease-models/