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 ParsonsPenny Huggins, Kevin Jeffrey Barnham, Robert A Cherny

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36 Citations (Scopus)

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

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