2. Academic Validation
  3. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing

Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing

  • Nat Commun. 2019 Apr 18;10(1):1817. doi: 10.1038/s41467-019-09494-2.
Farah H Siddiqi 1 2,  Fiona M Menzies 1,  Ana Lopez 1 3,  Eleanna Stamatakou 1 2,  Cansu Karabiyik 1,  Rodrigo Ureshino 1 3,  Thomas Ricketts 1,  Maria Jimenez-Sanchez 1 4,  Miguel Angel Esteban 5,  Liangxue Lai 5,  Micky D Tortorella 5,  Zhiwei Luo 5,  Hao Liu 5,  Emmanouil Metzakopian 6,  Hugo J R Fernandes 6,  Andrew Bassett 7,  Eric Karran 8,  Bruce L Miller 9,  Angeleen Fleming 1 3,  David C Rubinsztein 10 11
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
  • 2 UK Dementia Research Institute, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
  • 3 Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK.
  • 4 Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, SE5 9RX, UK.
  • 5 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Science Park, 501530, Guangzhou, China.
  • 6 UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK.
  • 7 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
  • 8 AbbVie Inc., Foundational Neuroscience Center, 200 Sidney Street, Cambridge, MA, 02139, USA.
  • 9 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
  • 10 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. dcr1000@cam.ac.uk.
  • 11 UK Dementia Research Institute, Cambridge Institute for Medical Research, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. dcr1000@cam.ac.uk.
PMID: 31000720 DOI: 10.1038/s41467-019-09494-2
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.

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