Protection from neurodegeneration in the 6-hydroxydopamine (6-OHDA) model of Parkinson's with novel 1-hydroxypyridin-2-one metal chelators

Abstract

Brain iron accumulation has been associated with inciting the generation of oxidative stress in a host of chronic neurological diseases, including Parkinson's disease. Using the catecholaminergic neurotoxin 6-hydroxydopamine to lesion cellular dopaminergic pathways as a model of Parkinson's disease in culture, a selection of 1-hydroxypyridin-2-one (1,2-HOPO) metal chelators were synthesized and their neuroprotective properties were compared to the 3-hydroxypyridin-4-one; deferiprone (3,4-HOPO; DFP). Protection against 6-OHDA and iron insult by the novel compounds 6 and 9 was comparable to DFP. Iron associated changes by 6-OHDA imply that the neuroprotective capacity of these compounds are due to chelation of the neuronal labile iron pool and the requirement of the iron binding moiety of compound 6 for efficacy supported this hypothesis. In conclusion, two novel 1,2-HOPO's and DFP have comparable neuroprotection against Parkinsonian-associated neurotoxins and supports the continued development of hydroxypyridinone compounds as a non-toxic therapeutic agent in the treatment of neurodegenerative disease.

Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents

“…To try and establish spectroscopic features that would allow us to distinguish an N 3 O 3 from an O 6 coordination mode, we were forced to first investigate by MS and NMR the complexation of Ga(III) on a model system. Compound 22 that we described for another type of application has been selected as such a model of ligand 19 [63].…”

“…It was considered that deprotection can be afforded under a range of relatively mild conditions by double bond isomerisation and subsequent hydrolysis without compromising other bonds in the chelator [62]. The key allyl protected 6-hydroxymethyl intermediate 17 was synthesised in five steps from commercially available 12 (Scheme 2) [63]. This hydroxymethyl derivative could then be converted to the novel chloromethyl derivative 17 by thionyl chloride for incorporation onto ligand cores.…”

Treating Alzheimer's disease by targeting iron

“…Deferiprone is an orally available iron chelator that is currently in clinical use and has been shown to cross the BBB. In animal models of Parkinson's disease, it has been shown to improve motor performance (Aguirre et al, 2015;Ayton, Lei, Duce, et al, 2013;Ayton, Lei, et al, 2015;Devos et al, 2014;Dexter et al, 2011;Workman et al, 2015). Deferiprone is neuroprotective in neuronal culture models of Aβ toxicity (Molina-Holgado, Gaeta, Francis, Williams, & Hider, 2008;Part et al, 2015), and it has been shown to reduce Aβ burden and tau phosphorylation in a rabbit model of AD (Prasanthi et al, 2012).…”

Activation of Nrf2 signaling by Icariin protects against 6‐OHDA‐induced neurotoxicity

“…Also, Nrf2 inactivation connected with aging that was the main risk factor for PD . In detail, Nrf2 was located in the cytosol of substantia nigra dopaminergic neurons, whereas in age‐matched neurodegenerative diseases patients . Furtherly, it was found in the nucleus of the Nrf2 signaling, represented by NQO1 and HO‐1 expressions, was upregulated, implying an attempt to enhance brain protection via this pathway .…”