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, 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.
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Bica
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia ; School of Chemistry, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia ; School of Chemistry, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Paterson
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia ; Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.affiliation: Department of Genetics, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Camakaris
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000737:chemistry*; D015032:Zinc / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013882:Thiosemicarbazones; D003300:Copper; D019703:Calcineurin; D015032:Zinc; D016559:Tacrolimus