Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.
Menzies, Fiona M
Tortorella, Micky D
Miller, Bruce L
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Siddiqi, F., Menzies, F. M., Lopez, A., Stamatakou, E., Karabiyik, C., Ureshino, R., Ricketts, T., et al. (2019). Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.. Nature communications, 10 (1), 1817. https://doi.org/10.1038/s41467-019-09494-2
Neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease and Huntington’s disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant -synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.
Cerebral Cortex, Neurons, Cell Line, Embryo, Nonmammalian, Animals, Mice, Inbred C57BL, Animals, Genetically Modified, Zebrafish, Swine, Swine, Miniature, Humans, Mice, Neurodegenerative Diseases, Disease Models, Animal, Felodipine, Neuroprotective Agents, Treatment Outcome, Mutation, Autophagy, Female, Male, alpha-Synuclein, Embryo, Mammalian, Induced Pluripotent Stem Cells, Drug Repositioning, Primary Cell Culture
Wellcome Trust (095317/Z/11/Z)
Alzheimer's Research UK (ARUK-TC2018-1)
Wellcome Trust (100140/Z/12/Z)
Embargo Lift Date
External DOI: https://doi.org/10.1038/s41467-019-09494-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290539