Metallothionein is a Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis

E-ISSN： 1873-4286|23|33|5001-5009

ISSN： 1381-6128

Source： Current Pharmaceutical Design, Vol.23, Iss.33, 2018-01, pp. : 5001-5009

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Abstract

Lou Gehrig#39;s disease, a synonym of amyotrophic lateral sclerosis, is an adult-onset lethalneurodegenerative disorder. Irrespective of extensive efforts to elucidate the pathogenesis of the disease andsearches for therapies, no favorable pharmacotherapeutic strategies have yet to be proposed. In a popular rodentmodel of ALS, G93A SOD1 strain of mouse, intracellular copper conditions were geared toward copperaccumulation inside cells, resulting in an acceleration of oxidative stress and apoptotic process. Disruption ofintracellular copper homeostasis was common to transgenic mice expressing human mutant SOD1s. In thisreview, the novel hypothesis that disruption of intracellular copper homeostasis could be involved in thedevelopment of the disease was introduced. Based upon the hypothesis, therapeutic outcomes of agents that arecapable of correcting and/or modifying intracellular copper homeostasis are described. Administration ofammonium tetrathiomolybdate, a selective intracellular copper chelator, delayed onset, slowed progression, andprolonged survival of a rodent model of the disease (G93A SOD1 mice). Metallothionein is a low molecularweight, cysteine-rich, metal-binding cytoplasmic protein that has beneficial properties in detoxification of toxicheavy metals, homeostatic regulation of intracellular essential trace elements, including copper, antioxidant, andantiapoptotic roles. In animal experiments of the G93A SOD1 mice, an increase of metallothionein proteins bymeans of induction by exercise or dexamethasone, genetic overexpression, or intraperitoneal administration, allresulted in a preferable outcome. The therapeutic effects were not inferior to those of approved drugs for ALS inhumans. These observations suggest that metallothionein could be worth investigating the therapeutic potential inclinical use.