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

Metallomics : Integrated Biometal Science
David G WorkmanJames A Duce

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.

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Citations

Aug 2, 2018·CNS Drugs·Dilan Athauda, Thomas Foltynie
Jan 12, 2019·British Journal of Pharmacology·Sara NiksereshtScott Ayton
Feb 23, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Tao ZhouRobert C Hider
Jan 9, 2020·Journal of Neural Transmission·David DevosUNKNOWN FAIRPARK-II and FAIRALS-II studygroups
May 8, 2020·Oxidative Medicine and Cellular Longevity·Monika PichlaIzabela Sadowska-Bartosz
Mar 21, 2019·Biotechnology and Applied Biochemistry·Li ZhuFeng Zhang
Mar 30, 2021·Oxidative Medicine and Cellular Longevity·Wei WuHaimin Chen
Oct 8, 2020·Journal of Medicinal Chemistry·Xiaoying JiangYuanyuan Xie

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