ZFIN ID: ZDB-PUB-190529-1
Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing
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.
Date: 2019
Source: Nature communications   10: 1817 (Journal)
Registered Authors: Fleming, Angeleen
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Autophagy/drug effects*
  • Cell Line
  • Cerebral Cortex/cytology
  • Cerebral Cortex/pathology
  • Disease Models, Animal
  • Drug Repositioning*
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Felodipine/pharmacology*
  • Felodipine/therapeutic use
  • Female
  • Humans
  • Induced Pluripotent Stem Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neurodegenerative Diseases/drug therapy*
  • Neurodegenerative Diseases/genetics
  • Neurodegenerative Diseases/pathology
  • Neurons/drug effects
  • Neurons/pathology
  • Neuroprotective Agents/pharmacology*
  • Neuroprotective Agents/therapeutic use
  • Primary Cell Culture
  • Swine
  • Swine, Miniature
  • Treatment Outcome
  • Zebrafish
  • alpha-Synuclein/genetics
  • alpha-Synuclein/metabolism
PubMed: 31000720 Full text @ Nat. Commun.
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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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