Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing

Farah H. Siddiqi, Fiona M. Menzies, Ana Lopez, Eleanna Stamatakou, Cansu Karabiyik, Rodrigo Ureshino, Thomas Ricketts, Maria Jimenez-Sanchez, Miguel Angel Esteban, Liangxue Lai, Micky D. Tortorella, Zhiwei Luo, Hao Liu, Emmanouil Metzakopian, Hugo J. R. Fernandes, Andrew Bassett, Eric Karran, Bruce L. Miller, Angeleen Fleming and David C. Rubinsztein ()
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Farah H. Siddiqi: University of Cambridge
Fiona M. Menzies: University of Cambridge
Ana Lopez: University of Cambridge
Eleanna Stamatakou: University of Cambridge
Cansu Karabiyik: University of Cambridge
Rodrigo Ureshino: University of Cambridge
Thomas Ricketts: University of Cambridge
Maria Jimenez-Sanchez: University of Cambridge
Miguel Angel Esteban: Chinese Academy of Sciences
Liangxue Lai: Chinese Academy of Sciences
Micky D. Tortorella: Chinese Academy of Sciences
Zhiwei Luo: Chinese Academy of Sciences
Hao Liu: Chinese Academy of Sciences
Emmanouil Metzakopian: University of Cambridge
Hugo J. R. Fernandes: University of Cambridge
Andrew Bassett: Wellcome Genome Campus
Eric Karran: AbbVie Inc., Foundational Neuroscience Center
Bruce L. Miller: University of California
Angeleen Fleming: University of Cambridge
David C. Rubinsztein: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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 α-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.

Date: 2019
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DOI: 10.1038/s41467-019-09494-2

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