The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease.
PBN-AR
Instytucja
Instytut Biochemii i Biofizyki Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
Acta Neuropathologica Communications
ISSN
EISSN
2051-5960
Wydawca
BioMed Central
DOI
URL
Rok publikacji
2017
Numer zeszytu
Strony od-do
53
Numer tomu
5
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
EN
Synucleinopathy;
Drug development;
Chelation;
Oxidative stress;
Neuroprotection
Open access
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Wersja ostateczna autora
Licencja otwartego dostępu
Creative Commons — Uznanie autorstwa
Czas opublikowania w otwartym dostępie
Razem z publikacją
Data udostępnienia w sposób otwarty
2017-06-28
Streszczenia
Język
EN
Treść
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 alpha-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 alpha-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T alpha-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.
Inne
System-identifier
PX-59e75eb1d5de40fbd4cff039
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