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.

• Authors: 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, Izabela A Zawisza, Ewa Kurowska, Andrew L Gundlach, Sheri Ma, Ashley I Bush, Dominic J Hare, Philip A Doble, Simon Crawford, Elisabeth Cl Gautier, Jack Parsons, Penny Huggins, Kevin J Barnham, Robert A Cherny
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 5 Issue 1 Pg. 53 (06 28 2017) ISSN: 2051-5960 [Electronic] England
• PMID: 28659169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 8-hydroxyquinazolin-4(3H)-one
• Antiparkinson Agents
• Cation Transport Proteins
• Neuroprotective Agents
• Quinazolinones
• Recombinant Proteins
• SNCA protein, human
• alpha-Synuclein
• metal transporting protein 1
• Oxidopamine
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Iron

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Animals
• Antiparkinson Agents (pharmacology)
• Cation Transport Proteins (metabolism)
• Cell Line, Tumor
• Dogs
• Female
• Humans
• Iron (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects, physiology)
• Oxidopamine
• Parkinsonian Disorders (drug therapy, metabolism, pathology)
• Quinazolinones (pharmacology)
• Rats
• Recombinant Proteins (genetics, metabolism)
• Substantia Nigra (drug effects, metabolism, pathology)
• alpha-Synuclein (genetics, metabolism)