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Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model

The Journal of biological chemistry, 2011-12, Vol.286 (51), p.44035-44044 [Peer Reviewed Journal]

2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2011 by The American Society for Biochemistry and Molecular Biology, Inc. 2011 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M111.274407 ;PMID: 22033929

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Title:
Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model
Author: Soon, Cynthia P.W. ; Donnelly, Paul S. ; Turner, Bradley J. ; Hung, Lin W. ; Crouch, Peter J. ; Sherratt, Nicki A. ; Tan, Jiang-Li ; Lim, Nastasia K.-H. ; Lam, Linh ; Bica, Laura ; Lim, SinChun ; Hickey, James L. ; Morizzi, Julia ; Powell, Andrew ; Finkelstein, David I. ; Culvenor, Janetta G. ; Masters, Colin L. ; Duce, James ; White, Anthony R. ; Barnham, Kevin J. ; Li, Qiao-Xin
Subjects: Amyotrophic Lateral Sclerosis ; Amyotrophic Lateral Sclerosis - metabolism ; Animals ; Antioxidants - chemistry ; Astrocytes - cytology ; Copper - chemistry ; CuII(atsm) ; Disease Models, Animal ; DNA-Binding Proteins - pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia - cytology ; Neurobiology ; Neurodegenerative Diseases ; Neurodegenerative Diseases - embryology ; Neurons - metabolism ; Organometallic Compounds - chemistry ; Oxidative Stress ; Oxygen - chemistry ; Peroxynitrite ; Peroxynitrous Acid - metabolism ; SODG93A ; Spinal Cord - pathology ; Superoxide Dismutase (SOD) ; Superoxide Dismutase - genetics ; Superoxide Dismutase-1 ; TDP-43 ; Thiosemicarbazones - chemistry ; Transgenes ; Transgenic Mice
Is Part Of: The Journal of biological chemistry, 2011-12, Vol.286 (51), p.44035-44044
Description: 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. Background: CuII(atsm) [(diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)] was orally administrated to transgenic SOD1G93A mice. Results: Treatment significantly prolonged lifespan with preservation of motor neurons. Reduced protein oxidation, attenuated astrocyte, and microglial activation also resulted from treatment. Conclusion: CuII(atsm) is neuroprotective in this model even when treatment begins after the onset of disease symptoms. Significance: The drug has therapeutic potential for amyotrophic lateral sclerosis.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M111.274407
PMID: 22033929
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model

2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2011 by The American Society for Biochemistry and Molecular Biology, Inc. 2011 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M111.274407 ;PMID: 22033929

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