Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation

Laura Bica, Jeffrey R. Liddell, Paul S. Donnelly, Clare Duncan, Aphrodite Caragounis, Irene Volitakis, Brett M. Paterson, Roberto Cappai, Alexandra Grubman, James Camakaris, Peter J. Crouch, Anthony R White

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato) -copper complex, CuII(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that CuII(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, CuII(atsm), but at a higher concentration. Induction of neurite elongation by CuII(gtsm) was restricted to neurites within the length range of 75-99 μm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM CuII(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that CuII(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM CuII(gtsm), suggesting a potential link between CuII(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.
Original languageEnglish
Article numbere90070
Number of pages13
JournalPLoS ONE
Volume9
Issue number2
DOIs
Publication statusPublished - 28 Feb 2014
Externally publishedYes

Cite this

Bica, L., Liddell, J. R., Donnelly, P. S., Duncan, C., Caragounis, A., Volitakis, I., ... White, A. R. (2014). Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation. PLoS ONE, 9(2), [e90070]. https://doi.org/10.1371/journal.pone.0090070
Bica, Laura ; Liddell, Jeffrey R. ; Donnelly, Paul S. ; Duncan, Clare ; Caragounis, Aphrodite ; Volitakis, Irene ; Paterson, Brett M. ; Cappai, Roberto ; Grubman, Alexandra ; Camakaris, James ; Crouch, Peter J. ; White, Anthony R. / Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation. In: PLoS ONE. 2014 ; Vol. 9, No. 2.
@article{6523e9dae8414607ad4438e797fc6619,
title = "Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation",
abstract = "Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato) -copper complex, CuII(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that CuII(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, CuII(atsm), but at a higher concentration. Induction of neurite elongation by CuII(gtsm) was restricted to neurites within the length range of 75-99 μm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM CuII(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that CuII(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM CuII(gtsm), suggesting a potential link between CuII(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.",
author = "Laura Bica and Liddell, {Jeffrey R.} and Donnelly, {Paul S.} and Clare Duncan and Aphrodite Caragounis and Irene Volitakis and Paterson, {Brett M.} and Roberto Cappai and Alexandra Grubman and James Camakaris and Crouch, {Peter J.} and White, {Anthony R}",
year = "2014",
month = "2",
day = "28",
doi = "10.1371/journal.pone.0090070",
language = "English",
volume = "9",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

Bica, L, Liddell, JR, Donnelly, PS, Duncan, C, Caragounis, A, Volitakis, I, Paterson, BM, Cappai, R, Grubman, A, Camakaris, J, Crouch, PJ & White, AR 2014, 'Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation' PLoS ONE, vol. 9, no. 2, e90070. https://doi.org/10.1371/journal.pone.0090070

Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation. / Bica, Laura; Liddell, Jeffrey R.; Donnelly, Paul S.; Duncan, Clare; Caragounis, Aphrodite; Volitakis, Irene; Paterson, Brett M.; Cappai, Roberto; Grubman, Alexandra; Camakaris, James; Crouch, Peter J.; White, Anthony R.

In: PLoS ONE, Vol. 9, No. 2, e90070, 28.02.2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation

AU - Bica, Laura

AU - Liddell, Jeffrey R.

AU - Donnelly, Paul S.

AU - Duncan, Clare

AU - Caragounis, Aphrodite

AU - Volitakis, Irene

AU - Paterson, Brett M.

AU - Cappai, Roberto

AU - Grubman, Alexandra

AU - Camakaris, James

AU - Crouch, Peter J.

AU - White, Anthony R

PY - 2014/2/28

Y1 - 2014/2/28

N2 - Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato) -copper complex, CuII(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that CuII(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, CuII(atsm), but at a higher concentration. Induction of neurite elongation by CuII(gtsm) was restricted to neurites within the length range of 75-99 μm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM CuII(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that CuII(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM CuII(gtsm), suggesting a potential link between CuII(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.

AB - Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato) -copper complex, CuII(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that CuII(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, CuII(atsm), but at a higher concentration. Induction of neurite elongation by CuII(gtsm) was restricted to neurites within the length range of 75-99 μm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM CuII(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that CuII(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM CuII(gtsm), suggesting a potential link between CuII(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.

UR - http://www.scopus.com/inward/record.url?scp=84896526305&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0090070

DO - 10.1371/journal.pone.0090070

M3 - Article

VL - 9

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 2

M1 - e90070

ER -

Bica L, Liddell JR, Donnelly PS, Duncan C, Caragounis A, Volitakis I et al. Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation. PLoS ONE. 2014 Feb 28;9(2). e90070. https://doi.org/10.1371/journal.pone.0090070