PUBLICATION

Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing

Authors
Siddiqi, F.H., Menzies, F.M., Lopez, A., Stamatakou, E., Karabiyik, C., Ureshino, R., Ricketts, T., Jimenez-Sanchez, M., Esteban, M.A., Lai, L., Tortorella, M.D., Luo, Z., Liu, H., Metzakopian, E., Fernandes, H.J.R., Bassett, A., Karran, E., Miller, B.L., Fleming, A., Rubinsztein, D.C.
ID
ZDB-PUB-190529-1
Date
2019
Source
Nature communications   10: 1817 (Journal)
Registered Authors
Fleming, Angeleen
Keywords
none
MeSH Terms
  • Zebrafish
  • Mice, Inbred C57BL
  • Treatment Outcome
  • Male
  • Felodipine/pharmacology*
  • Felodipine/therapeutic use
  • Swine
  • Cerebral Cortex/cytology
  • Cerebral Cortex/pathology
  • Embryo, Nonmammalian
  • Drug Repositioning*
  • Neuroprotective Agents/pharmacology*
  • Neuroprotective Agents/therapeutic use
  • Neurodegenerative Diseases/drug therapy*
  • Neurodegenerative Diseases/genetics
  • Neurodegenerative Diseases/pathology
  • Mice
  • Animals, Genetically Modified
  • alpha-Synuclein/genetics
  • alpha-Synuclein/metabolism
  • Induced Pluripotent Stem Cells
  • Mutation
  • Cell Line
  • Animals
  • Embryo, Mammalian
  • Disease Models, Animal
  • Female
  • Neurons/drug effects
  • Neurons/pathology
  • Humans
  • Autophagy/drug effects*
  • Primary Cell Culture
  • Swine, Miniature
(all 33)
PubMed
31000720 Full text @ Nat. Commun.
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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-153 .
Genes / Markers
Figures
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Expression
No data available
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cu7TgTransgenic Insertion
    cu10TgTransgenic Insertion
      s1101tEtTransgenic Insertion
        sa14768
          Point Mutation
          1 - 4 of 4
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          Human Disease / Model
          Human Disease Fish Conditions Evidence
          tauopathycu7TgcontrolTAS
          tauopathycu10Tg; s1101tEtcontrolTAS
          1 - 2 of 2
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          Sequence Targeting Reagents
          No data available
          Fish
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab1-maptmonoclonal
            IgG1Mouse
            Ab3-tubamonoclonal
              IgG1Mouse
              1 - 2 of 2
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              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              Dendra2EFGDendra2
              EGFPEFGEGFP
              GAL4EFGGAL4
              1 - 3 of 3
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              Mapping
              No data available