title: Beneficial Effects of Multitarget Iron Chelator on Central Nervous System and Gastrocnemius Muscle in SOD1(G93A) Transgenic ALS Mice.
abstract: Accumulation of evidence has demonstrated high levels of iron in the central nervous system of both sporadic and familial amyotrophic lateral sclerosis (ALS) patients and in ALS mouse models. In accordance, iron chelation therapy was found to exert beneficial effects on ALS mice. Our group has designed and synthesized series of multifunctional non-toxic, brain permeable iron-chelating compounds for neurodegenerative diseases. Recent study has shown that co-administration of one of these drugs, VAR10303 with high calorie/energy-supplemented diet (VAR-ced), initiated after the appearance of disease symptoms improved motor performance, extended survival, and attenuated iron accumulation and motoneuron loss in SOD1(G93A) mice. Since VAR was found to exert diverse pharmacological properties associated with mitochondrial biogenesis in the gastrocnemius (GNS) muscle, we further assessed in the current study the impact of VAR-ced on additional neurorescue-associated molecular targets in the GNS and frontal cortex in SOD1(G93A) mice. The results show that VAR-ced treatment upregulated the expression of various HIF-1α-target glycolytic genes and elevated the levels of Bcl-2, neurotrophic factors, and AKT/GSK3β signaling in the GNS and frontal cortex of SOD1(G93A) mice, suggesting that these protective regulatory parameters regulated by VAR-ced treatment may be associated with the beneficial effects of the drug observed on ALS mice.
authors.affiliation: Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
authors.forename: Sagit
authors.initials: S
authors.lastname: Golko-Perez
authors.affiliation: Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.affiliation: Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.affiliation: Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel. worly@tx.technion.ac.il.
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006912:Hydroxyquinolines / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072105:Superoxide Dismutase-1 / Q000235:genetics
chemical_list: C000602792:5-(2-(methylprop-2-ynylamino)ethyl)quinolin-8-ol; C497443:Hif1a protein, mouse; D006912:Hydroxyquinolines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Amyotrophic lateral sclerosis; Iron chelation; Neurorescue; SOD1G93A mice