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
-
- Humans
- alpha-Synuclein/genetics
- alpha-Synuclein/metabolism
- Drug Repositioning*
- Embryo, Mammalian
- Autophagy/drug effects*
- Neurodegenerative Diseases/drug therapy*
- Neurodegenerative Diseases/genetics
- Neurodegenerative Diseases/pathology
- Male
- Swine
- Mice, Inbred C57BL
- Swine, Miniature
- Induced Pluripotent Stem Cells
- Neuroprotective Agents/pharmacology*
- Neuroprotective Agents/therapeutic use
- Cerebral Cortex/cytology
- Cerebral Cortex/pathology
- Mice
- Embryo, Nonmammalian
- Animals
- Female
- Felodipine/pharmacology*
- Felodipine/therapeutic use
- Treatment Outcome
- Animals, Genetically Modified
- Cell Line
- Disease Models, Animal
- Zebrafish
- Mutation
- Neurons/drug effects
- Neurons/pathology
- Primary Cell Culture
- PubMed
- 31000720 Full text @ Nat. Commun.
Citation
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. (2019) Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nature communications. 10:1817.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping