CuII(atsm) Attenuates Neuroinflammation

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 & 3 others Jari Koistinaho, Anthony R. White, Katja M. Kanninen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number668
Number of pages14
JournalFrontiers in Neuroscience
Volume12
DOIs
Publication statusPublished - 24 Sep 2018

Keywords

  • Astrocyte
  • Copper
  • Inflammation
  • Microglia
  • Neurodegeneration

Cite this

Choo, X. Y., Liddell, J. R., Huuskonen, M. T., Grubman, A., Moujalled, D., Roberts, J., ... Kanninen, K. M. (2018). CuII(atsm) Attenuates Neuroinflammation. Frontiers in Neuroscience, 12, [668]. https://doi.org/10.3389/fnins.2018.00668
Choo, Xin Yi ; Liddell, Jeffrey R. ; Huuskonen, Mikko T. ; Grubman, Alexandra ; Moujalled, Diane ; Roberts, Jessica ; Kysenius, Kai ; Patten, Lauren ; Quek, Hazel ; Oikari, Lotta E. ; Duncan, Clare ; James, Simon A. ; Mcinnes, Lachlan E. ; Hayne, David J. ; Donnelly, Paul S. ; Pollari, Eveliina ; Vähätalo, Suvi ; Lejavová, Katarína ; Kettunen, Mikko I. ; Malm, Tarja ; Koistinaho, Jari ; White, Anthony R. ; Kanninen, Katja M. / CuII(atsm) Attenuates Neuroinflammation. In: Frontiers in Neuroscience. 2018 ; Vol. 12.
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title = "CuII(atsm) Attenuates Neuroinflammation",
abstract = "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.",
keywords = "Astrocyte, Copper, Inflammation, Microglia, Neurodegeneration",
author = "Choo, {Xin Yi} and Liddell, {Jeffrey R.} and Huuskonen, {Mikko T.} and Alexandra Grubman and Diane Moujalled and Jessica Roberts and Kai Kysenius and Lauren Patten and Hazel Quek and Oikari, {Lotta E.} and Clare Duncan and James, {Simon A.} and Mcinnes, {Lachlan E.} and Hayne, {David J.} and Donnelly, {Paul S.} and Eveliina Pollari and Suvi V{\"a}h{\"a}talo and Katar{\'i}na Lejavov{\'a} and Kettunen, {Mikko I.} and Tarja Malm and Jari Koistinaho and White, {Anthony R.} and Kanninen, {Katja M.}",
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Choo, XY, Liddell, JR, Huuskonen, MT, Grubman, A, Moujalled, D, Roberts, J, Kysenius, K, Patten, L, Quek, H, Oikari, LE, Duncan, C, James, SA, Mcinnes, LE, Hayne, DJ, Donnelly, PS, Pollari, E, Vähätalo, S, Lejavová, K, Kettunen, MI, Malm, T, Koistinaho, J, White, AR & Kanninen, KM 2018, 'CuII(atsm) Attenuates Neuroinflammation', Frontiers in Neuroscience, vol. 12, 668. https://doi.org/10.3389/fnins.2018.00668

CuII(atsm) Attenuates Neuroinflammation. / Choo, Xin Yi; Liddell, Jeffrey R.; Huuskonen, Mikko T.; Grubman, Alexandra; Moujalled, Diane; Roberts, Jessica; Kysenius, Kai; Patten, Lauren; Quek, Hazel; Oikari, Lotta E.; Duncan, Clare; James, Simon A.; Mcinnes, Lachlan E.; Hayne, David J.; Donnelly, Paul S.; Pollari, Eveliina; Vähätalo, Suvi; Lejavová, Katarína; Kettunen, Mikko I.; Malm, Tarja; Koistinaho, Jari; White, Anthony R.; Kanninen, Katja M.

In: Frontiers in Neuroscience, Vol. 12, 668, 24.09.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CuII(atsm) Attenuates Neuroinflammation

AU - Choo, Xin Yi

AU - Liddell, Jeffrey R.

AU - Huuskonen, Mikko T.

AU - Grubman, Alexandra

AU - Moujalled, Diane

AU - Roberts, Jessica

AU - Kysenius, Kai

AU - Patten, Lauren

AU - Quek, Hazel

AU - Oikari, Lotta E.

AU - Duncan, Clare

AU - James, Simon A.

AU - Mcinnes, Lachlan E.

AU - Hayne, David J.

AU - Donnelly, Paul S.

AU - Pollari, Eveliina

AU - Vähätalo, Suvi

AU - Lejavová, Katarína

AU - Kettunen, Mikko I.

AU - Malm, Tarja

AU - Koistinaho, Jari

AU - White, Anthony R.

AU - Kanninen, Katja M.

PY - 2018/9/24

Y1 - 2018/9/24

N2 - 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.

AB - 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.

KW - Astrocyte

KW - Copper

KW - Inflammation

KW - Microglia

KW - Neurodegeneration

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U2 - 10.3389/fnins.2018.00668

DO - 10.3389/fnins.2018.00668

M3 - Article

VL - 12

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-453X

M1 - 668

ER -

Choo XY, Liddell JR, Huuskonen MT, Grubman A, Moujalled D, Roberts J et al. CuII(atsm) Attenuates Neuroinflammation. Frontiers in Neuroscience. 2018 Sep 24;12. 668. https://doi.org/10.3389/fnins.2018.00668