title: Additive Neuroprotective Effects of the Multifunctional Iron Chelator M30 with Enriched Diet in a Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-γ (PPARγ)-co activator 1 alpha (PGC-1α), PPARγ, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS.
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: Silvia
authors.initials: S
authors.lastname: Mandel
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: Lana
authors.initials: L
authors.lastname: Kupershmidt
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: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D006912:Hydroxyquinolines / Q000008:administration & dosage*; D007502:Iron Chelating Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010648:Phenylacetates / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D015306:Biogenic Monoamines; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010648:Phenylacetates; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D015102:3,4-Dihydroxyphenylacetic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008995:Monoamine Oxidase
keywords: Amyotrophic lateral sclerosis; Calorie energy supplemented diet; Gastrocnemius muscle; MAO inhibitor/iron chelator; Mitochondrial biogenesis/metabolism; SOD1-G93A mice