Therapeutic effects of Cu^II(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.

Key words::

• Amyotrophic lateral sclerosis (ALS)
• diacetylbis(4-methylthiosemicarbazone)-copper^II [Cu^II(atsm)]
• riluzole
• rotarod
• therapeutic

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by the Australian National Health and Medical Research Council (NHMRC) Project Grant 1005651, The University of Melbourne, The Motor Neurone Disease Research Institute of Australia, and the Australian Research Council (ARC). None of these funding bodies contributed to study design, the collection, analysis and interpretation of data, writing the report, or the decision to submit the article for publication.