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
Copyright policy )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 A‐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)‐la and HIF‐target genes (enolasel and vascular endothe‐lial 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, L., Weinreb, O., Amit, T., Mandel, S., Carri, M. T., Youdim, M. B. H. 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. FASEBJ. 23, 3766‐3779 (2009). www.fasebj.org
Vascular Endothelial Growth Factor A, 572, Neuroprotective Agent, Apoptosis, Mice, Transgenic, Neurite, Motor Neuron, alpha Subunit, Iron Chelating Agents, Transgenic, Cell Line, Glycogen Synthase Kinase 3, Mice, GAP-43 Protein, Receptors, Neurites, Animals, Extracellular Signal-Regulated MAP Kinases, Piperazine, Hydroxyquinoline, Settore BIO/10 - BIOCHIMICA, Motor Neurons, Glycogen Synthase Kinase 3 beta, Extracellular Signal-Regulated MAP Kinase, Animal, Superoxide Dismutase, Brain-Derived Neurotrophic Factor, Amyotrophic Lateral Sclerosis, Transferrin, Apoptosi, Cell Differentiation, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Iron Chelating Agent, Disease Models, Animal, Phosphopyruvate Hydratase, Molsidomine, Disease Models, Hydroxyquinolines, Hypoxia-Inducible Factor 1, Proto-Oncogene Proteins c-akt, Amyotrophic Lateral Sclerosi, Signal Transduction
Vascular Endothelial Growth Factor A, 572, Neuroprotective Agent, Apoptosis, Mice, Transgenic, Neurite, Motor Neuron, alpha Subunit, Iron Chelating Agents, Transgenic, Cell Line, Glycogen Synthase Kinase 3, Mice, GAP-43 Protein, Receptors, Neurites, Animals, Extracellular Signal-Regulated MAP Kinases, Piperazine, Hydroxyquinoline, Settore BIO/10 - BIOCHIMICA, Motor Neurons, Glycogen Synthase Kinase 3 beta, Extracellular Signal-Regulated MAP Kinase, Animal, Superoxide Dismutase, Brain-Derived Neurotrophic Factor, Amyotrophic Lateral Sclerosis, Transferrin, Apoptosi, Cell Differentiation, Hydrogen Peroxide, Hypoxia-Inducible Factor 1, alpha Subunit, Iron Chelating Agent, Disease Models, Animal, Phosphopyruvate Hydratase, Molsidomine, Disease Models, Hydroxyquinolines, Hypoxia-Inducible Factor 1, Proto-Oncogene Proteins c-akt, Amyotrophic Lateral Sclerosi, Signal Transduction
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