Targeting dysregulation of brain iron homeostasis in Parkinson's disease by iron chelators

• Published in: Free radical biology & medicine Vol. 62; pp. 52 - 64
• Main Authors: Weinreb, Orly, Mandel, Silvia, Youdim, Moussa B.H., Amit, Tamar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013
• Subjects: amine oxidase (flavin-containing); antioxidants; Brain; chelating agents; Free radicals; Free Radicals - metabolism; genes; homeostasis; Homeostasis - drug effects; Humans; Iron; Iron - metabolism; Iron Chelating Agents - administration & dosage; Iron chelation; Neuroprotection; Neuroprotective Agents - administration & dosage; Parkinson disease; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; reactive oxygen species; Reactive Oxygen Species - metabolism; signal transduction; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; TfR; Brain; Iron chelation; Neuroprotection; BBB; Parkinson's disease; EPO; ALS; 6-OHDA; HO-1; Iron; DFO; PHD; Tf; L-DOPA; UPDRS; UPS; GSH; AD; Free radicals; HIF; OS; EGCG; VEGF; SNpc; SOD; PD; TH; ROS; MAO; MPTP; FBXL5; IRE; prolyl-4-hydroxylase; transferrin; transferrin receptor; amyotrophic lateral sclerosis; blood–brain barrier; iron-responsive element; Alzheimer's disease; monoamine oxidase; Unified Parkinson's Disease Rating Scale; ubiquitin–proteasome system; heme oxygenase-1; tyrosine hydroxylase; superoxide dismutase; N-methyl-4-phenyl-1,2,3,6-tertahydropyridine; glutathione; reactive oxygen species; epigallocatechin 3-gallate; erythropoietin; F-box/leucine-rich repeat protein 5, GLUT, glucose transporter; l-dihydroxyphenylalanine; hypoxia-inducible factor; substantia nigra pars compacta; 6-hydroxydopamine; desferrioxamine; vascular endothelial growth factor; oxidative stress
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2013.01.017

Brain iron accumulation has been implicated in a host of chronic neurological diseases, including Parkinson's disease (PD). The elevated iron levels observed in the substantia nigra of PD subjects have been suggested to incite the generation of reactive oxygen species and intracellular α-synuclein aggregation, terminating in the oxidative neuronal destruction of this brain area. Thus, elucidation of the molecular mechanisms involved in iron dysregulation and oxidative stress-induced neurodegeneration is a crucial step in deciphering PD pathology and in developing novel iron-complexing compounds aimed at restoring brain iron homeostasis and attenuating neurodegeneration. This review discusses the involvement of dysregulation of brain iron homeostasis in PD pathology, with an emphasis on the potential effectiveness of naturally occurring compounds and novel iron-chelating/antioxidant therapeutic hybrid molecules, exerting a spectrum of neuroprotective interrelated activities: antioxidant/monoamine oxidase inhibition, activation of the hypoxia-inducible factor (HIF)-1 signaling pathway, induction of HIF-1 target iron-regulatory and antioxidative genes, and inhibition of α-synuclein accumulation and aggregation. [Display omitted] ► Brain iron dyshomeostasis in PD is an essential factor in the disease pathology. ► Brain iron accumulation involves an increase in iron-containing molecules. ► Iron induces oxidative stress. ► Iron induces α-synuclein aggregation and accumulation. ► Natural and chimeric iron chelators display potential benefits in PD animal models.