Neuroprotective Copper Bis(thiosemicarbazonato) Complexes Promote Neurite Elongation

被引:40
作者
Bica, Laura [1 ]
Liddell, Jeffrey R. [1 ]
Donnelly, Paul S. [2 ,3 ]
Duncan, Clare [1 ]
Caragounis, Aphrodite [1 ]
Volitakis, Irene [4 ]
Paterson, Brett M. [2 ,3 ]
Cappai, Roberto [1 ,2 ]
Grubman, Alexandra [1 ]
Camakaris, James [5 ]
Crouch, Peter J. [1 ,4 ]
White, Anthony R. [1 ,4 ]
机构
[1] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia
[2] Bio21 Mol Sci & Biotechnol Inst, Parkville, Vic, Australia
[3] Univ Melbourne, Sch Chem, Melbourne, Vic, Australia
[4] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia
[5] Univ Melbourne, Dept Genet, Melbourne, Vic, Australia
来源
PLOS ONE | 2014年 / 9卷 / 02期
基金
澳大利亚研究理事会; 英国医学研究理事会;
关键词
AMYLOID-BETA-PEPTIDE; NERVE GROWTH-FACTOR; MAP KINASE KINASE; N-TERMINAL KINASE; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; PC12; CELLS; A-BETA; TRANSGENIC MICE; CYCLOSPORINE-A;
D O I
10.1371/journal.pone.0090070
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu m 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.
引用
收藏
页数:13
相关论文
共 57 条
[1]   Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ [J].
Adlard, Paul A. ;
Cherny, Robert A. ;
Finkelstein, David I. ;
Gautier, Elisabeth ;
Robb, Elysia ;
Cortes, Mikhalina ;
Volitakis, Irene ;
Liu, Xiang ;
Smith, Jeffrey P. ;
Perez, Keyla ;
Laughton, Katrina ;
Li, Qiao-Xin ;
Charman, Susan A. ;
Nicolazzo, Joseph A. ;
Wilkins, Simon ;
Deleva, Karolina ;
Lynch, Toni ;
Kok, Gaik ;
Ritchie, Craig W. ;
Tanzi, Rudolph E. ;
Cappai, Roberto ;
Masters, Colin L. ;
Barnham, Kevin J. ;
Bush, Ashley I. .
NEURON, 2008, 59 (01) :43-55
[2]   Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease [J].
Adlard, Paul A. ;
Bica, Laura ;
White, Anthony R. ;
Nurjono, Milawaty ;
Filiz, Gulay ;
Crouch, Peter J. ;
Donnelly, Paul S. ;
Cappai, Roberto ;
Finkelstein, David I. ;
Bush, Ashley I. .
PLOS ONE, 2011, 6 (03)
[3]   Metals in Alzheimer's and Parkinson's diseases [J].
Barnham, Kevin J. ;
Bush, Ashley I. .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2008, 12 (02) :222-228
[4]  
Beraldo H, 1998, TRANSIT METAL CHEM, V23, P67
[5]   Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex [J].
Bica, Laura ;
Meyerowitz, Jodi ;
Parker, Sarah J. ;
Caragounis, Aphrodite ;
Du, Tai ;
Paterson, Brett M. ;
Barnham, Kevin J. ;
Crouch, Peter J. ;
White, Anthony R. ;
Donnelly, Paul S. .
BIOMETALS, 2011, 24 (01) :117-133
[6]   NGF promotes copper accumulation required for optimum neurite outgrowth and protein methylation [J].
Birkaya, B ;
Aletta, JM .
JOURNAL OF NEUROBIOLOGY, 2005, 63 (01) :49-61
[7]   Structural trends in copper(II) bis(thiosemicarbazone) radiopharmaceuticals [J].
Blower, PJ ;
Castle, TC ;
Cowley, AR ;
Dilworth, JR ;
Donnelly, PS ;
Labisbal, E ;
Sowrey, FE ;
Teat, SJ ;
Went, MJ .
DALTON TRANSACTIONS, 2003, (23) :4416-4425
[8]   THE SYNTHESIS AND STRUCTURE OF ENCAPSULATING LIGANDS - PROPERTIES OF BICYCLIC HEXAMINES [J].
BOTTOMLEY, GA ;
CLARK, IJ ;
CREASER, II ;
ENGELHARDT, LM ;
GEUE, RJ ;
HAGEN, KS ;
HARROWFIELD, JM ;
LAWRANCE, GA ;
LAY, PA ;
SARGESON, AM ;
SEE, AJ ;
SKELTON, BW ;
WHITE, AH ;
WILNER, FR .
AUSTRALIAN JOURNAL OF CHEMISTRY, 1994, 47 (01) :143-179
[9]   Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice [J].
Cherny, RA ;
Atwood, CS ;
Xilinas, ME ;
Gray, DN ;
Jones, WD ;
McLean, CA ;
Barnham, KJ ;
Volitakis, I ;
Fraser, FW ;
Kim, YS ;
Huang, XD ;
Goldstein, LE ;
Moir, RD ;
Lim, JT ;
Beyreuther, K ;
Zheng, H ;
Tanzi, RE ;
Masters, CL ;
Bush, AI .
NEURON, 2001, 30 (03) :665-676
[10]   Axon pathology in neurological disease: a neglected therapeutic target [J].
Coleman, MP ;
Perry, VH .
TRENDS IN NEUROSCIENCES, 2002, 25 (10) :532-537