CuII(atsm) Attenuates Neuroinflammation.

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

doi:10.3389/fnins.2018.00668

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.

Highlights

Chronic neuroinflammation, manifested by increased activation of glial cells and excessive production of pro-inflammatory mediators, is one of the hallmark pathological features of several neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis, PD, and amyotrophic lateral sclerosis (ALS)
In AD, X-ray fluorescence (XRF) analyses have shown that amyloid plaques are enriched for copper and zinc (Miller et al, 2006), yet several studies have demonstrated that many important regions such as the neocortex are copper deficient in AD patient brains (Schrag et al, 2011; Rembach et al, 2013; Graham et al, 2014)
Peripheral inflammation induced by LPS triggers an inflammatory response that is characterized by increased expression of pro-inflammatory cytokines in the brain and plasma (Thomson et al, 2014)

Summary

Introduction

Chronic neuroinflammation, manifested by increased activation of glial cells and excessive production of pro-inflammatory mediators, is one of the hallmark pathological features of several neurodegenerative diseases, including AD, multiple sclerosis, PD, and ALS. In AD, X-ray fluorescence (XRF) analyses have shown that amyloid plaques are enriched for copper and zinc (Miller et al, 2006), yet several studies have demonstrated that many important regions such as the neocortex are copper deficient in AD patient brains (Schrag et al, 2011; Rembach et al, 2013; Graham et al, 2014). Both the sequestration of copper in plaques and loss of copperdependent functions have been proposed to contribute to AD pathology. 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

Results

Conclusion