Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model.

Autor: Soon CPW; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010., Donnelly PS; School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010., Turner BJ; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010; Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria 3010., Hung LW; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010., Crouch PJ; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010., Sherratt NA; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010., Tan JL; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010., Lim NK; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010., Lam L; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010., Bica L; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010., Lim S; School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010., Hickey JL; School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010., Morizzi J; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia., Powell A; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia., Finkelstein DI; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010., Culvenor JG; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010., Masters CL; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010., Duce J; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010., White AR; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010., Barnham KJ; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010. Electronic address: kbarnham@unimelb.edu.au., Li QX; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010. Electronic address: q.li@unimelb.edu.au.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2011 Dec 23; Vol. 286 (51), pp. 44035-44044. Date of Electronic Publication: 2011 Oct 27.
DOI: 10.1074/jbc.M111.274407
Abstrakt: Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
Databáze: MEDLINE
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