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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Animals
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Apoptosis / drug effects
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Brain-Derived Neurotrophic Factor / biosynthesis
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Cell Differentiation / drug effects
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Cell Line
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Disease Models, Animal
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Extracellular Signal-Regulated MAP Kinases / metabolism
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GAP-43 Protein / biosynthesis
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hydrogen Peroxide / toxicity
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Hydroxyquinolines / therapeutic use
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Iron Chelating Agents / therapeutic use*
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Mice
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Mice, Transgenic
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Molsidomine / analogs & derivatives
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Molsidomine / toxicity
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Motor Neurons / drug effects*
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Motor Neurons / metabolism
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Neurites / drug effects
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Neurites / physiology
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Neuroprotective Agents / therapeutic use*
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Phosphopyruvate Hydratase / biosynthesis
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Piperazines / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Transferrin / biosynthesis
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Signal Transduction / drug effects
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Superoxide Dismutase / toxicity
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Superoxide Dismutase-1
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline
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Brain-Derived Neurotrophic Factor
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GAP-43 Protein
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Hif1a protein, mouse
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Hydroxyquinolines
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Hypoxia-Inducible Factor 1, alpha Subunit
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Iron Chelating Agents
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Neuroprotective Agents
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Piperazines
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Receptors, Transferrin
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Vascular Endothelial Growth Factor A
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5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol
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linsidomine
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Hydrogen Peroxide
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Molsidomine
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Glycogen Synthase Kinase 3
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Eno1 protein, mouse
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Phosphopyruvate Hydratase