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

David I. Finkelstein, Jessica L. Billings, Paul A Adlard, Scott Ayton, Amelia Sedjahtera, Colin Louis Masters, Simon Wilkins, David Shackleford, Susan Ann Charman, Wojciech Bal, Izabela A. Zawisza, Ewa Kurowska, Andrew L Gundlach, Sherie Ma, Ashley Ian Bush, Dominic J. Hare, Philip A. Doble, Simon Andrew Crawford, Elisabeth Cl Gautier, Jack Parsons & 3 others Penny Huggins, Kevin Jeffrey Barnham, Robert A Cherny

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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. Invivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra parscompacta 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.
Original languageEnglish
Article number53
Number of pages16
JournalActa neuropathologica communications
Volume5
Issue number1
DOIs
Publication statusPublished - 28 Jun 2017

Keywords

  • Synucleinopathy
  • Drug development
  • Chelation
  • Oxidative stress
  • Neuroprotection

Cite this

Finkelstein, David I. ; Billings, Jessica L. ; Adlard, Paul A ; Ayton, Scott ; Sedjahtera, Amelia ; Masters, Colin Louis ; Wilkins, Simon ; Shackleford, David ; Charman, Susan Ann ; Bal, Wojciech ; Zawisza, Izabela A. ; Kurowska, Ewa ; Gundlach, Andrew L ; Ma, Sherie ; Bush, Ashley Ian ; Hare, Dominic J. ; Doble, Philip A. ; Crawford, Simon Andrew ; Gautier, Elisabeth Cl ; Parsons, Jack ; Huggins, Penny ; Barnham, Kevin Jeffrey ; Cherny, Robert A. / The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. In: Acta neuropathologica communications. 2017 ; Vol. 5, No. 1.
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abstract = "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. Invivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra parscompacta 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.",
keywords = "Synucleinopathy, Drug development, Chelation, Oxidative stress, Neuroprotection",
author = "Finkelstein, {David I.} and Billings, {Jessica L.} and Adlard, {Paul A} and Scott Ayton and Amelia Sedjahtera and Masters, {Colin Louis} and Simon Wilkins and David Shackleford and Charman, {Susan Ann} and Wojciech Bal and Zawisza, {Izabela A.} and Ewa Kurowska and Gundlach, {Andrew L} and Sherie Ma and Bush, {Ashley Ian} and Hare, {Dominic J.} and Doble, {Philip A.} and Crawford, {Simon Andrew} and Gautier, {Elisabeth Cl} and Jack Parsons and Penny Huggins and Barnham, {Kevin Jeffrey} and Cherny, {Robert A}",
year = "2017",
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doi = "10.1186/s40478-017-0456-2",
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Finkelstein, DI, Billings, JL, Adlard, PA, Ayton, S, Sedjahtera, A, Masters, CL, Wilkins, S, Shackleford, D, Charman, SA, Bal, W, Zawisza, IA, Kurowska, E, Gundlach, AL, Ma, S, Bush, AI, Hare, DJ, Doble, PA, Crawford, SA, Gautier, EC, Parsons, J, Huggins, P, Barnham, KJ & Cherny, RA 2017, 'The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease' Acta neuropathologica communications, vol. 5, no. 1, 53. https://doi.org/10.1186/s40478-017-0456-2

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 Louis; Wilkins, Simon; Shackleford, David; Charman, Susan Ann; Bal, Wojciech; Zawisza, Izabela A.; Kurowska, Ewa; Gundlach, Andrew L; Ma, Sherie; Bush, Ashley Ian; Hare, Dominic J.; Doble, Philip A.; Crawford, Simon Andrew; Gautier, Elisabeth Cl; Parsons, Jack; Huggins, Penny; Barnham, Kevin Jeffrey; Cherny, Robert A.

In: Acta neuropathologica communications, Vol. 5, No. 1, 53, 28.06.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Finkelstein, David I.

AU - Billings, Jessica L.

AU - Adlard, Paul A

AU - Ayton, Scott

AU - Sedjahtera, Amelia

AU - Masters, Colin Louis

AU - Wilkins, Simon

AU - Shackleford, David

AU - Charman, Susan Ann

AU - Bal, Wojciech

AU - Zawisza, Izabela A.

AU - Kurowska, Ewa

AU - Gundlach, Andrew L

AU - Ma, Sherie

AU - Bush, Ashley Ian

AU - Hare, Dominic J.

AU - Doble, Philip A.

AU - Crawford, Simon Andrew

AU - Gautier, Elisabeth Cl

AU - Parsons, Jack

AU - Huggins, Penny

AU - Barnham, Kevin Jeffrey

AU - Cherny, Robert A

PY - 2017/6/28

Y1 - 2017/6/28

N2 - 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. Invivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra parscompacta 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.

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KW - Synucleinopathy

KW - Drug development

KW - Chelation

KW - Oxidative stress

KW - Neuroprotection

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