Evidence map›Paper›PMID 28659169›Full record

ArticleActa neuropathologica communications2017

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 L Masters, Simon Wilkins, David M Shackleford, Susan A Charman, Wojciech Bal and 13 more

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 67 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed, 1 pooled it
6.7field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

67 citing papers in PubMed, 1 synthesis or guideline pooled it, 98 citations in OpenAlex.

  1. Next-generation pharmacological strategies for Parkinson's disease: a systematic literature review of symptom management and disease modification.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Pooled it
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  5. Copper Homeostasis and Cuproptosis in Neurological Disorders.Drug design, development and therapy · 2026
    Review
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  17. Recent Advances in Clinical Trials in Multiple System Atrophy.Current neurology and neuroscience reports · 2024
    Review
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  20. Article

7 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

23 authors at 6 institutions in 2 countries.

David I FinkelsteinThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia. d.finkelstein@florey.edu.au.ORCID 0000-0002-8167-4917
Jessica L BillingsThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Paul A AdlardThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Scott AytonThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Amelia SedjahteraThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Colin L MastersThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Simon WilkinsThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
David M ShacklefordCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
Susan A CharmanCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
Wojciech BalThe Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Izabela A ZawiszaThe Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Ewa KurowskaThe Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Andrew L GundlachThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Sheri MaThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Ashley I BushThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Dominic J HareThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Philip A DobleElemental Bio-imaging Facility, The University of Technology Sydney, Broadway, Ultimo, NSW, 2007, Australia.
Simon CrawfordAustralia Electron Microscope Unit, School of Biosciences, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Elisabeth Cl GautierPrana Biotechnology Ltd, Parkville, VIC, 3052, Australia.
Jack ParsonsPrana Biotechnology Ltd, Parkville, VIC, 3052, Australia.
Penny HugginsPrana Biotechnology Ltd, Parkville, VIC, 3052, Australia.
Kevin J BarnhamThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Robert A ChernyThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia. rcherny@unimelb.edu.au.
The University of Melbourne · AUInstitute of Biochemistry and Biophysics, Polish Academy of Sciences · PLPrana Biotechnology (Australia) · AUMonash University · AUUniversity of Technology Sydney · AUFlorey Institute of Neuroscience and Mental Health · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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. 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.

Indexed as

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinealpha-SynucleinAnimalsAntiparkinson AgentsCation Transport ProteinsCell Line, TumorDogsFemaleFerroportinHumansIronMaleMice, Inbred C57BLMice, TransgenicNeuronsNeuroprotective Agents1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine8-hydroxyquinazolin-4(3H)-onealpha-SynucleinAntiparkinson AgentsCation Transport ProteinsFerroportinIronNeuroprotective AgentsOxidopamineQuinazolinonesRecombinant ProteinsSNCA protein, humanChelationDrug developmentNeuroprotectionOxidative stressSynucleinopathy

Identifiers

PMID28659169
PMCPMC5490188
OpenAlexW2726077464

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.