title: Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis.
abstract: Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple central nervous system targets. We have recently synthesized multifunctional, nontoxic, brain-permeable iron-chelating drugs, M30 and HLA20, possessing the N-propargylamine neuroprotective moiety of rasagiline (Azilect) and the iron-chelating moiety of VK28. The present study demonstrates that M30 and HLA20 possess a wide range of pharmacological activities in mouse NSC-34 motor neuron cells, including neuroprotective effects against hydrogen peroxide- and 3-morpholinosydnonimine-induced neurotoxicity, induction of differentiation, and up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes (enolase1 and vascular endothelial growth factor). Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by PD98059 and GF109203X, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. A major finding was the ability of M30 to significantly extend the survival of G93A-SOD1 amyotrophic lateral sclerosis mice and delay the onset of the disease. These properties of the novel multimodal iron-chelating drugs possessing neuroprotective/neuritogenic activities may offer future therapeutic possibilities for motor neurodegenerative diseases.
authors.affiliation: Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Haifa, Israel
authors.forename: Lana
authors.initials: L
authors.lastname: Kupershmidt
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: Maria Teresa
authors.initials: MT
authors.lastname: Carri
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019922:GAP-43 Protein / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide / Q000633:toxicity; D006912:Hydroxyquinolines / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000096:biosynthesis; D010879:Piperazines / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011990:Receptors, Transferrin / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000633:toxicity; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D019208:Brain-Derived Neurotrophic Factor; D019922:GAP-43 Protein; C497443:Hif1a protein, mouse; D006912:Hydroxyquinolines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010879:Piperazines; D011990:Receptors, Transferrin; D042461:Vascular Endothelial Growth Factor A; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C457379:Eno1 protein, mouse; D010751:Phosphopyruvate Hydratase