title: Novel therapeutic approach for neurodegenerative pathologies: multitarget iron-chelating drugs regulating hypoxia-inducible factor 1 signal transduction pathway.
abstract: Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1). HIF-1 is a 'master switch' being an important physiological response mechanism, likely enhancing neuroprotective compensatory pathways involved in many physiological processes within the brain. This mini-review will discuss the multifunctional mechanisms of action of the drugs, M30 and HLA20 in preclinical models of neurodegeneration with a specific emphasis on their ability to activate the HIF-1 signal transduction pathway.
authors.affiliation: Eve Topf Centers of Excellence for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Rappaport Family Research Institute, Technion Faculty of Medicine, Haifa, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.forename: Silvia
authors.initials: S
authors.lastname: Mandel
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000818:Animals; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents