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.
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.
Kupershmidt
Lana
L
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Haifa, Israel
Weinreb
Orly
O
Amit
Tamar
T
Mandel
Silvia
S
Carri
Maria Teresa
MT
Youdim
Moussa B H
MB
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
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