Journal
FASEB JOURNAL
Volume 23, Issue 11, Pages 3766-3779Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-130047
Keywords
motor neurodegenerative diseases; hypoxia-inducible factor; differentiation; G93A-SOD1 ALS mouse model
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Funding
- The Israeli ALS Research Association (Haifa, Israel)
- Technion-Research and Development and Rappaport Family Research Institute, Technion-Israel Institute of Technology (Haifa, Israel)
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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)-1 alpha 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, 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. FASEB J. 23, 3766-3779 (2009). www.fasebj.org
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