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

Finkelstein, DI; Billings, JL; Adlard, PA; Ayton, S; Sedjahtera, A; Masters, CL; Wilkins, S; Shackleford, DM; Charman, SA; Bal, W; Zawisza, IA; Kurowska, E; Gundlach, AL; Ma, S; Bush, AI; Hare, DJ; Doble, PA; Crawford, S; Gautier, EC; Parsons, J; Huggins, P; Barnham, KJ; Cherny, RA

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

Finkelstein, DI Billings, JL Adlard, PA Ayton, S Sedjahtera, A Masters, CL Wilkins, S Shackleford, DM Charman, SA Bal, W Zawisza, IA Kurowska, E Gundlach, AL Ma, S Bush, AI Hare, DJ

Doble, PA

Crawford, S Gautier, EC Parsons, J Huggins, P Barnham, KJ Cherny, RA

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Publication Type:: Journal Article
Citation:: Acta neuropathologica communications, 2017, 5 (1), pp. 53 - ?
Issue Date:: 2017-06-28

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Field	Value	Language
dc.contributor.author	Finkelstein, DI	en_US
dc.contributor.author	Billings, JL	en_US
dc.contributor.author	Adlard, PA	en_US
dc.contributor.author	Ayton, S	en_US
dc.contributor.author	Sedjahtera, A	en_US
dc.contributor.author	Masters, CL	en_US
dc.contributor.author	Wilkins, S	en_US
dc.contributor.author	Shackleford, DM	en_US
dc.contributor.author	Charman, SA	en_US
dc.contributor.author	Bal, W	en_US
dc.contributor.author	Zawisza, IA	en_US
dc.contributor.author	Kurowska, E	en_US
dc.contributor.author	Gundlach, AL	en_US
dc.contributor.author	Ma, S	en_US
dc.contributor.author	Bush, AI	en_US
dc.contributor.author	Hare, DJ https://orcid.org/0000-0002-5922-7643	en_US
dc.contributor.author	Doble, PA https://orcid.org/0000-0002-8472-1301	en_US
dc.contributor.author	Crawford, S	en_US
dc.contributor.author	Gautier, EC	en_US
dc.contributor.author	Parsons, J	en_US
dc.contributor.author	Huggins, P	en_US
dc.contributor.author	Barnham, KJ	en_US
dc.contributor.author	Cherny, RA	en_US
dc.date.available	2017-06-14	en_US
dc.date.issued	2017-06-28	en_US
dc.identifier.citation	Acta neuropathologica communications, 2017, 5 (1), pp. 53 - ?	en_US
dc.identifier.uri	http://hdl.handle.net/10453/115242
dc.description.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.	en_US
dc.relation.ispartof	Acta neuropathologica communications	en_US
dc.relation.isbasedon	10.1186/s40478-017-0456-2	en_US
dc.subject.mesh	Substantia Nigra	en_US
dc.subject.mesh	Neurons	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Transgenic	en_US
dc.subject.mesh	Dogs	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Rats	en_US
dc.subject.mesh	Parkinsonian Disorders	en_US
dc.subject.mesh	Iron	en_US
dc.subject.mesh	Oxidopamine	en_US
dc.subject.mesh	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine	en_US
dc.subject.mesh	Cation Transport Proteins	en_US
dc.subject.mesh	Recombinant Proteins	en_US
dc.subject.mesh	Antiparkinson Agents	en_US
dc.subject.mesh	Neuroprotective Agents	en_US
dc.subject.mesh	Oxidative Stress	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	alpha-Synuclein	en_US
dc.subject.mesh	Quinazolinones	en_US
dc.title	The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	5	en_US
utslib.for	0301 Analytical Chemistry	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1109 Neurosciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFS - Centre for Forensic Science
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	5	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/115242