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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2018.00668


  • 1The University of Melbourne, Australia
  • 2Monash University, Australia
  • 3Florey Institute of Neuroscience and Mental Health, Australia
  • 4A.I. Virtanen Institute for Molecular Sciences, Univeristy of Eastern Finland, Finland
  • 5QIMR Berghofer Medical Research Institute, Australia
  • 6Australian Synchrotron, Australia
  • 7Bio21 Institute, University of Melbourne, Australia

Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer’s disease. Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation.
Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex CuII(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro.
Results: By using a sophisticated in vivo magnetic resonance imaging approach we report the efficacy of CuII(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide. CuII(atsm) also induced anti-inflammatory outcomes in primary microglia (significant reductions in nitric oxide (NO), MCP-1 and TNF) and astrocytes (significantly reduced NO, MCP-1 and IL-6) in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 in microglia and astrocytes.
Conclusions: The beneficial effects of CuII(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.

Keywords: Microglia, astrocyte, Inflammation, neurodegeneration, Copper

Received: 14 Feb 2018; Accepted: 05 Sep 2018.

Edited by:

Wendy Noble, King's College London, United Kingdom

Reviewed by:

Einar M. Sigurdsson, New York University, United States
Jessica L. Teeling, University of Southampton, United Kingdom  

Copyright: © 2018 Choo, Grubman, Huuskonen, Moujalled, Roberts, Kysenius, Patten, Quek, Oikari, Duncan, James, McInnes, Hayne, Donnelly, Pollari, Vähätalo, Lejavová, Kettunen, Malm, Liddell, Koistinaho, White and Kanninen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Katja M. Kanninen, A.I. Virtanen Institute for Molecular Sciences, Univeristy of Eastern Finland, Kuopio, Finland,