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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0456-2) contains supplementary material, which is available to authorized users.

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

“…; Finkelstein et al . ). Dichlorofluorescein diacetate (DCF; Molecular Probes, Eugene, OR, USA) was dissolved in dimethyl sulphoxide (Sigma‐Aldrich, Castle Hill, NSW, Australia) to a concentration of 5 mM in an argon‐purged atmosphere.…”

“…The ability of L-DOPA and CQ to inhibit Fe-mediated production of hydrogen peroxide (H 2 O 2 ) was measured using a modified indirect fluorescence detection assay (Opazo et al 2002;Finkelstein et al 2017). Dichlorofluorescein diacetate (DCF; Molecular Probes, Eugene, OR, USA) was dissolved in dimethyl sulphoxide (Sigma-Aldrich, Castle Hill, NSW, Australia) to a concentration of 5 mM in an argon-purged atmosphere.…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…In these mouse models of PD, PBT434 was able to rescue dopaminergic cell loss in the SN, which translated by an improvement in motor behavior. Most importantly, PBT434 decreased the levels of α-syn in either MPTP and human A53T α-syn mice [446]. This molecule shows promise as it is a low-binding chelator and could thus have less side-effects compared to other chelators.…”

MSA: From basic mechanisms to experimental therapeutics

“…The small molecule iron chaperone PBT-434, a novel quinazolinone inhibitor of iron-mediated protein accumulation and aggregation [127], has also shown encouraging preliminary results in PLP-hα-syn mice, reducing α-syn aggregation and GCIs, preserving SN neurons and improving motor function in MSA mice [125]. PBT434 is thought to act by redistributing reactive iron across membranes, thereby blocking intracellular protein aggregation and oxidative stress [127]. A phase I trial with PBT434 in healthy volunteers is currently ongoing (U1111-1211-0052) [128].…”