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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

Lana Kupershmidt^*,, Orly Weinreb^*,, Tamar Amit^*,, Silvia Mandel^*,, Maria Teresa Carri^, and Moussa B. H. Youdim^*,,1

^* Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and

Department of Pharmacology, Rappaport Family Research Institute, Faculty of Medicine, Technion, Haifa, Israel;

Laboratory of Neurochemistry, Fondazione Santa Lucia Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; and

Department of Biology, University of Rome Tor Vergata, Rome, Italy

¹ Correspondence: Department of Pharmacology, Technion-Faculty of Medicine, P.O. Box 9697, 31096 Haifa, Israel. E-mail: youdim{at}tx.technion.ac.il

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 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.

Key Words: motor neurodegenerative diseases • hypoxia-inducible factor • differentiation • G93A-SOD1 ALS mouse model