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

Abstract

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.

Keywords: 6-OHDA; 6-hydroxydopamine; AD; ALS; Alzheimer's disease; BBB; Brain; DFO; EGCG; EPO; F-box/leucine-rich repeat protein 5, GLUT, glucose transporter; FBXL5; Free radicals; GSH; HIF; HO-1; IRE; Iron; Iron chelation; L-DOPA; MAO; MPTP; N-methyl-4-phenyl-1,2,3,6-tertahydropyridine; Neuroprotection; OS; PD; PHD; Parkinson's disease; ROS; SNpc; SOD; TH; Tf; TfR; UPDRS; UPS; Unified Parkinson's Disease Rating Scale; VEGF; amyotrophic lateral sclerosis; blood–brain barrier; desferrioxamine; epigallocatechin 3-gallate; erythropoietin; glutathione; heme oxygenase-1; hypoxia-inducible factor; iron-responsive element; l-dihydroxyphenylalanine; monoamine oxidase; oxidative stress; prolyl-4-hydroxylase; reactive oxygen species; substantia nigra pars compacta; superoxide dismutase; transferrin; transferrin receptor; tyrosine hydroxylase; ubiquitin–proteasome system; vascular endothelial growth factor..