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

Author:

Finkelstein David I.ORCID,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.

Abstract

AbstractElevated 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.

Funder

State Government of Victoria

National Health and Medical Research Council

Michael J. Fox Foundation for Parkinson's Research

Parkinson's United Kingdom

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine

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