Journal Article

Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation

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

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alzheimer's disease / Alzheimers disease / Animal cognition / Animal models / Animals / Axonogenesis / Axons / Biology / Biotechnology / Calcineurin / Calcineurin - metabolism / Calcineurin Inhibitors / Calcineurin phosphatase / Cell culture / Clioquinol / Coordination Complexes - chemical synthesis / Coordination Complexes - pharmacology / Coordination compounds / Copper / Copper - chemistry / Copper - metabolism / Copper compounds / Elongation / Enzyme Inhibitors - pharmacology / Growth factors / Health aspects / Homeostasis / Inhibition / Ionophores / Kinases / Medical research / Medicine / Medicine, Experimental / Memory / Mental health / Metals / Motor neuron diseases / Movement disorders / Nervous system diseases / Neurites - drug effects / Neurites - enzymology / Neurites - ultrastructure / Neurodegeneration / Neurodegenerative diseases / Neurophysiology / Neuroprotection / Neuroprotective Agents - chemical synthesis / Neuroprotective Agents - pharmacology / Neurosciences / Parkinson's disease / Parkinsons disease / Pathology / PC12 Cells / Pheochromocytoma cells / Phosphatase / Phosphatases / Proteins / Rats / Rodents / Studies / Tacrolimus / Tacrolimus - pharmacology / Thiosemicarbazones - chemistry / Zinc / Zinc - metabolism