Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing

Farah H Siddiqi,Andrew Bassett,Hugo J R Fernandes,Rodrigo Portes Ureshino ,Fiona M Menzies,Maria Jimenez-Sanchez,Angeleen Fleming,Eleanna Stamatakou,Bruce L Miller,Ana López ,Thomas C Ricketts ,Eric Karran,Miguel A Esteban ,Hao Líu ,Micky D Tortorella,Cansu Karabiyik,Liangxue Lai,Zhiwei Luo,Emmanouil Metzakopian,David C Rubinsztein

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.

Highlights

From a screen of a library enriched in approved drugs, we identified verapamil, an L-type calcium channel blocker, as an inducer of autophagosome formation and validated that L-type calcium channels are an mTOR-independent autophagy target using numerous tools[6]
In order to select the most promising of the L-type calcium channel blockers (Table 1) for further in vivo studies, we researched all currently prescribed FDA-approved members of this family[7] and ranked them according to blood–brain barrier (BBB)-penetration, structural similarity and known half-life in man
LC3 is recruited to the membrane of forming autophagosomes and is widely accepted to be a reliable marker of autophagic vesicles

Summary

Introduction

From a screen of a library enriched in approved drugs, we identified verapamil, an L-type calcium channel blocker, as an inducer of autophagosome formation and validated that L-type calcium channels are an mTOR-independent autophagy target using numerous tools[6]. L-type calcium channel blockers are anti-hypertensive drugs and are widely used in man for long-term therapeutic treatment. We screened a panel of currently prescribed L-type calcium channel blockers to identify a BBB-penetrant member of this class that showed strong autophagy-inducing effects and had a long half-life in man. Our data reveal that felodipine administration in mice at concentrations approximating those seen in humans induces autophagy and reduces levels of neurotoxic proteins, like A53T αsynuclein. These data suggest that this drug may have efficacy in humans with appropriate neurodegenerative diseases that may be ameliorated by autophagy induction

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