Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model.
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.
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010.
Cynthia P W
CPW
Soon
School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010.
Paul S
PS
Donnelly
Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010; Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria 3010.
Bradley J
BJ
Turner
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.
Lin W
LW
Hung
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.
Peter J
PJ
Crouch
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.
Nicki A
NA
Sherratt
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010.
Jiang-Li
JL
Tan
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.
Nastasia K-H
NK
Lim
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010.
Linh
L
Lam
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010.
Laura
L
Bica
School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010.
SinChun
S
Lim
School of Chemistry, The University of Melbourne, Parkville, Victoria 3010; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010.
James L
JL
Hickey
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Julia
J
Morizzi
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Andrew
A
Powell
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010.
David I
DI
Finkelstein
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010; Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010.
Janetta G
JG
Culvenor
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010.
Colin L
CL
Masters
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010.
James
J
Duce
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.
Anthony R
AR
White
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.
Kevin J
KJ
Barnham
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.
Qiao-Xin
QX
Li
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001253:Astrocytes / Q000166:cytology; D056831:Coordination Complexes; D003300:Copper / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology; D019636:Neurodegenerative Diseases / Q000196:embryology; D009474:Neurons / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D030421:Peroxynitrous Acid / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013882:Thiosemicarbazones / Q000737:chemistry*; D019076:Transgenes
D000975:Antioxidants; D056831:Coordination Complexes; D004268:DNA-Binding Proteins; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D030421:Peroxynitrous Acid; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D010100:Oxygen