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The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease

Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb ess...

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Autores principales: Finkelstein, David I., Billings, Jessica L., Adlard, Paul A., Ayton, Scott, Sedjahtera, Amelia, Masters, Colin L., Wilkins, Simon, Shackleford, David M., Charman, Susan A., Bal, Wojciech, Zawisza, Izabela A, Kurowska, Ewa, Gundlach, Andrew L., Ma, Sheri, Bush, Ashley I., Hare, Dominic J., Doble, Philip A., Crawford, Simon, Gautier, Elisabeth CL., Parsons, Jack, Huggins, Penny, Barnham, Kevin J., Cherny, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490188/
https://www.ncbi.nlm.nih.gov/pubmed/28659169
http://dx.doi.org/10.1186/s40478-017-0456-2
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author Finkelstein, David I.
Billings, Jessica L.
Adlard, Paul A.
Ayton, Scott
Sedjahtera, Amelia
Masters, Colin L.
Wilkins, Simon
Shackleford, David M.
Charman, Susan A.
Bal, Wojciech
Zawisza, Izabela A
Kurowska, Ewa
Gundlach, Andrew L.
Ma, Sheri
Bush, Ashley I.
Hare, Dominic J.
Doble, Philip A.
Crawford, Simon
Gautier, Elisabeth CL.
Parsons, Jack
Huggins, Penny
Barnham, Kevin J.
Cherny, Robert A.
author_facet Finkelstein, David I.
Billings, Jessica L.
Adlard, Paul A.
Ayton, Scott
Sedjahtera, Amelia
Masters, Colin L.
Wilkins, Simon
Shackleford, David M.
Charman, Susan A.
Bal, Wojciech
Zawisza, Izabela A
Kurowska, Ewa
Gundlach, Andrew L.
Ma, Sheri
Bush, Ashley I.
Hare, Dominic J.
Doble, Philip A.
Crawford, Simon
Gautier, Elisabeth CL.
Parsons, Jack
Huggins, Penny
Barnham, Kevin J.
Cherny, Robert A.
author_sort Finkelstein, David I.
collection PubMed
description Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-017-0456-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-54901882017-06-30 The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease Finkelstein, David I. Billings, Jessica L. Adlard, Paul A. Ayton, Scott Sedjahtera, Amelia Masters, Colin L. Wilkins, Simon Shackleford, David M. Charman, Susan A. Bal, Wojciech Zawisza, Izabela A Kurowska, Ewa Gundlach, Andrew L. Ma, Sheri Bush, Ashley I. Hare, Dominic J. Doble, Philip A. Crawford, Simon Gautier, Elisabeth CL. Parsons, Jack Huggins, Penny Barnham, Kevin J. Cherny, Robert A. Acta Neuropathol Commun Research Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-017-0456-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-06-28 /pmc/articles/PMC5490188/ /pubmed/28659169 http://dx.doi.org/10.1186/s40478-017-0456-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Finkelstein, David I.
Billings, Jessica L.
Adlard, Paul A.
Ayton, Scott
Sedjahtera, Amelia
Masters, Colin L.
Wilkins, Simon
Shackleford, David M.
Charman, Susan A.
Bal, Wojciech
Zawisza, Izabela A
Kurowska, Ewa
Gundlach, Andrew L.
Ma, Sheri
Bush, Ashley I.
Hare, Dominic J.
Doble, Philip A.
Crawford, Simon
Gautier, Elisabeth CL.
Parsons, Jack
Huggins, Penny
Barnham, Kevin J.
Cherny, Robert A.
The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title_full The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title_fullStr The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title_full_unstemmed The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title_short The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
title_sort novel compound pbt434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of parkinson’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490188/
https://www.ncbi.nlm.nih.gov/pubmed/28659169
http://dx.doi.org/10.1186/s40478-017-0456-2
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