Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.

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 r...

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Autores principales: 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
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Publicado: Public Library of Science (PLoS) 2014
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spelling oai:doaj.org-article:5344d4ebcc43491a8a4ad0efaafde9ce2021-11-18T08:30:25ZNeuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.1932-620310.1371/journal.pone.0090070https://doaj.org/article/5344d4ebcc43491a8a4ad0efaafde9ce2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24587210/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Abnormal 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, Cu(II)(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that Cu(II)(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, Cu(II)(atsm), but at a higher concentration. Induction of neurite elongation by Cu(II)(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 Cu(II)(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that Cu(II)(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 Cu(II)(gtsm), suggesting a potential link between Cu(II)(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.Laura BicaJeffrey R LiddellPaul S DonnellyClare DuncanAphrodite CaragounisIrene VolitakisBrett M PatersonRoberto CappaiAlexandra GrubmanJames CamakarisPeter J CrouchAnthony R WhitePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e90070 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
description 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, Cu(II)(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that Cu(II)(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, Cu(II)(atsm), but at a higher concentration. Induction of neurite elongation by Cu(II)(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 Cu(II)(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that Cu(II)(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 Cu(II)(gtsm), suggesting a potential link between Cu(II)(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes.
format article
author 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
author_facet 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
author_sort Laura Bica
title Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
title_short Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
title_full Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
title_fullStr Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
title_full_unstemmed Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
title_sort neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/5344d4ebcc43491a8a4ad0efaafde9ce
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