Apoptosis of cultured astrocytes induced by the copper and neocuproine complex through oxidative stress and JNK activation

Sung Ho Chen, Jen Kun Lin, Shing Hwa Liu, Yu Chih Liang, Shoei Yn Lin-shiau

研究成果: 雜誌貢獻文章

49 引文 (Scopus)

摘要

Astrocytes play a critical neurotrophic and neuroprotective role in the brain, and improper function of these cells may contribute to the onset of neurodegenerative diseases. Because astrocytes are known to be enriched with Cu chaperone proteins, it is important to understand the factors that may lead to cytotoxic effects of Cu on astrocytes. In this report, we demonstrated a dramatic potentiating effect of neocuproine (NCP), a membrane permeable metal chelator, on Cu, but not Fe or Pb, in inducing apoptosis of cultured astrocytes. It was estimated that individually, CuCl2 and NCP only weakly exhibited cytotoxic effects on astrocytes, with EC50 of 180 and 600 μM, respectively. However, NCP at a nontoxic concentration of 10μM markedly reduced EC50 of Cu to 0.35 μM (physiological concentration) and Cu (10 μM) reduced EC50 of NCP down to 0.06 μM. The mechanisms underlying these dramatic potentiation effects are elucidated. NCP increased the intracellular concentration of Cu in astrocytes and a nonpermeable Cu chelator, bathocuproine disulfonate was able to abolish all of the apoptotic signaling. Cell death was determined to be via apoptosis due to increased reactive oxygen species production, mitochondrial dysfunction, depletion of glutathione and adenosine triphosphate, cytochrome c release, c-Jun N-terminal kinase, and caspase-3 activation, and poly-ADP-ribose polymerase degradation. This finding, coupled with our previous reports, suggests that metal chelators (NCP, dithiocarbamate and disulfiram) should be cautiously used as they may potentiate a cytotoxic effect of endogenous Cu on astrocytes. Their clinical implications in the etiology of neurodegenerative diseases deserve further investigation.
原文英語
頁(從 - 到)138-149
頁數12
期刊Toxicological Sciences
102
發行號1
DOIs
出版狀態已發佈 - 三月 2008
對外發佈Yes

指紋

Oxidative stress
Astrocytes
Oxidative Stress
Chemical activation
Apoptosis
Chelating Agents
Neurodegenerative diseases
Neurodegenerative Diseases
Mitogen-Activated Protein Kinase 10
Metals
Disulfiram
Poly(ADP-ribose) Polymerases
Cell death
Cytochromes c
copper-neocuproine complex
Caspase 3
Glutathione
neocuproine
Reactive Oxygen Species
Brain

ASJC Scopus subject areas

  • Toxicology

引用此文

Apoptosis of cultured astrocytes induced by the copper and neocuproine complex through oxidative stress and JNK activation. / Chen, Sung Ho; Lin, Jen Kun; Liu, Shing Hwa; Liang, Yu Chih; Lin-shiau, Shoei Yn.

於: Toxicological Sciences, 卷 102, 編號 1, 03.2008, p. 138-149.

研究成果: 雜誌貢獻文章

Chen, Sung Ho ; Lin, Jen Kun ; Liu, Shing Hwa ; Liang, Yu Chih ; Lin-shiau, Shoei Yn. / Apoptosis of cultured astrocytes induced by the copper and neocuproine complex through oxidative stress and JNK activation. 於: Toxicological Sciences. 2008 ; 卷 102, 編號 1. 頁 138-149.
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abstract = "Astrocytes play a critical neurotrophic and neuroprotective role in the brain, and improper function of these cells may contribute to the onset of neurodegenerative diseases. Because astrocytes are known to be enriched with Cu chaperone proteins, it is important to understand the factors that may lead to cytotoxic effects of Cu on astrocytes. In this report, we demonstrated a dramatic potentiating effect of neocuproine (NCP), a membrane permeable metal chelator, on Cu, but not Fe or Pb, in inducing apoptosis of cultured astrocytes. It was estimated that individually, CuCl2 and NCP only weakly exhibited cytotoxic effects on astrocytes, with EC50 of 180 and 600 μM, respectively. However, NCP at a nontoxic concentration of 10μM markedly reduced EC50 of Cu to 0.35 μM (physiological concentration) and Cu (10 μM) reduced EC50 of NCP down to 0.06 μM. The mechanisms underlying these dramatic potentiation effects are elucidated. NCP increased the intracellular concentration of Cu in astrocytes and a nonpermeable Cu chelator, bathocuproine disulfonate was able to abolish all of the apoptotic signaling. Cell death was determined to be via apoptosis due to increased reactive oxygen species production, mitochondrial dysfunction, depletion of glutathione and adenosine triphosphate, cytochrome c release, c-Jun N-terminal kinase, and caspase-3 activation, and poly-ADP-ribose polymerase degradation. This finding, coupled with our previous reports, suggests that metal chelators (NCP, dithiocarbamate and disulfiram) should be cautiously used as they may potentiate a cytotoxic effect of endogenous Cu on astrocytes. Their clinical implications in the etiology of neurodegenerative diseases deserve further investigation.",
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AB - Astrocytes play a critical neurotrophic and neuroprotective role in the brain, and improper function of these cells may contribute to the onset of neurodegenerative diseases. Because astrocytes are known to be enriched with Cu chaperone proteins, it is important to understand the factors that may lead to cytotoxic effects of Cu on astrocytes. In this report, we demonstrated a dramatic potentiating effect of neocuproine (NCP), a membrane permeable metal chelator, on Cu, but not Fe or Pb, in inducing apoptosis of cultured astrocytes. It was estimated that individually, CuCl2 and NCP only weakly exhibited cytotoxic effects on astrocytes, with EC50 of 180 and 600 μM, respectively. However, NCP at a nontoxic concentration of 10μM markedly reduced EC50 of Cu to 0.35 μM (physiological concentration) and Cu (10 μM) reduced EC50 of NCP down to 0.06 μM. The mechanisms underlying these dramatic potentiation effects are elucidated. NCP increased the intracellular concentration of Cu in astrocytes and a nonpermeable Cu chelator, bathocuproine disulfonate was able to abolish all of the apoptotic signaling. Cell death was determined to be via apoptosis due to increased reactive oxygen species production, mitochondrial dysfunction, depletion of glutathione and adenosine triphosphate, cytochrome c release, c-Jun N-terminal kinase, and caspase-3 activation, and poly-ADP-ribose polymerase degradation. This finding, coupled with our previous reports, suggests that metal chelators (NCP, dithiocarbamate and disulfiram) should be cautiously used as they may potentiate a cytotoxic effect of endogenous Cu on astrocytes. Their clinical implications in the etiology of neurodegenerative diseases deserve further investigation.

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