title: Therapeutic effects of CuII(atsm) in the SOD1-G37R mouse model of amyotrophic lateral sclerosis.
abstract: Our objective was to assess the copper(II) complex of diacetylbis(4-methylthiosemicarbazone) [Cu(II)(atsm)] for its preclinical potential as a novel therapeutic for ALS. Experimental paradigms used were designed to assess Cu(II)(atsm) efficacy relative to treatment with riluzole, as a function of dose administered, and when administered post symptom onset. Mice expressing human Cu/Zn superoxide dismutase harbouring the disease-causing G37R mutation (SOD1-G37R) were used and effects of Cu(II)(atsm) determined by assessing mouse survival and locomotor function (rotarod assay). Cu(II)(atsm) improved SOD1-G37R mouse survival and locomotor function in a dose-dependent manner. The highest dose tested improved survival by 26%. Riluzole had a modest effect on mouse survival (3.3%) but it did not improve locomotor function. Cotreatment with Cu(II)(atsm) did not alter the protective activity of Cu(II)(atsm) administered on its own. Commencing treatment with Cu(II)(atsm) after the onset of symptoms was less effective than treatments that commenced before symptom onset but still significantly improved locomotor function and survival. Improved locomotor function and survival of SOD1-G37R mice supports the potential for Cu(II)(atsm) as a novel treatment option for ALS.
authors: Department of Pathology.
authors: Erin J
authors: EJ
authors: McAllum
authors: Nastasia K-H
authors: NK
authors: Lim
authors: James L
authors: JL
authors: Hickey
authors: Brett M
authors: BM
authors: Paterson
authors: Paul S
authors: PS
authors: Donnelly
authors: Qiao-Xin
authors: QX
authors: Li
authors: Jeffrey R
authors: JR
authors: Liddell
authors: Kevin J
authors: KJ
authors: Barnham
authors: Anthony R
authors: AR
authors: White
authors: Peter J
authors: PJ
authors: Crouch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D056831:Coordination Complexes; D003300:Copper / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000627:therapeutic use*; D011897:Random Allocation; D013482:Superoxide Dismutase / Q000235:genetics*; D013882:Thiosemicarbazones / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D003300:Copper; C470429:SOD1 G37R protein, mouse; D013482:Superoxide Dismutase