title: 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.
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, Tyne and Wear NE1 8ST, UK. david.tetard@northumbria.ac.uk.
authors.forename: David G
authors.initials: DG
authors.lastname: Workman
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsatsanis
authors.forename: Frank W
authors.initials: FW
authors.lastname: Lewis
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Maryam
authors.initials: M
authors.lastname: Mousadoust
authors.forename: Nishani T
authors.initials: NT
authors.lastname: Hettiarachchi
authors.forename: Michael
authors.initials: M
authors.lastname: Hunter
authors.forename: Chris S
authors.initials: CS
authors.lastname: Peers
authors.forename: David
authors.initials: D
authors.lastname: Tétard
authors.forename: James A
authors.initials: JA
authors.lastname: Duce
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D000077543:Deferiprone; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000517:prevention & control*; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C580946:1,2-hydroxypyridinone; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D011728:Pyridones; D000077543:Deferiprone; D016627:Oxidopamine