Abstract

Neuroinflammation has a major role in several brain disorders including Alzheimer's disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (Cu-II(gtsm) and Cu-II(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with Cu-II(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone-pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer's disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.

Authors	Choo, Xin Yi; McInnes, Lachlan E.; Grubman, Alexandra; Wasielewska, Joanna M.; Belaya, Irina; Burrows, Emma; Quek, Hazel; Martin, Jorge Canas; Loppi, Sanna; Sorvari, Annika; Rait, Dzhessi; Powell, Andrew; Duncan, Clare; Liddell, Jeffrey R.; Tanila, Heikki; Polo, Jose M.; Malm, Tarja; Kanninen, Katja M.; Donnelly, Paul S.; White, Anthony R.
Journal	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Pages
Volume	23
Date	1/01/2022
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.3390/ijms231810722