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posted on 24.09.2018, 04:15 authored by Xin Yi Choo, Jeffrey R. Liddell, Mikko T. Huuskonen, Alexandra Grubman, Diane Moujalled, Jessica Roberts, Kai Kysenius, Lauren Patten, Hazel Quek, Lotta E. Oikari, Clare Duncan, Simon A. James, Lachlan E. McInnes, David J. Hayne, Paul S. Donnelly, Eveliina Pollari, Suvi Vähätalo, Katarína Lejavová, Mikko I. Kettunen, Tarja Malm, Jari Koistinaho, Anthony R. White, Katja M. Kanninen

Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer’s disease (AD). 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 (MRI) approach, we report the efficacy of CuII(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). CuII(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes.

Conclusion: The beneficial effects of CuII(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.

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