title: The Copper bis(thiosemicarbazone) Complex CuII(atsm) Is Protective Against Cerebral Ischemia Through Modulation of the Inflammatory Milieu.
abstract: Developing new therapies for stroke is urgently needed, as this disease is the leading cause of death and disability worldwide, and the existing treatment is only available for a small subset of patients. The interruption of blood flow to the brain during ischemic stroke launches multiple immune responses, characterized by infiltration of peripheral immune cells, the activation of brain microglial cells, and the accumulation of immune mediators. Copper is an essential trace element that is required for many critical processes in the brain. Copper homeostasis is disturbed in chronic neurodegenerative diseases and altered in stroke patients, and targeted copper delivery has been shown to be protective against chronic neurodegeneration. This study was undertaken to assess whether the copper bis(thiosemicarbazone) complex, CuII(atsm), is beneficial in acute brain injury, in preclinical mouse models of ischemic stroke. We demonstrate that the copper complex CuII(atsm) protects neurons from excitotoxicity and N2a cells from OGD in vitro, and is protective in permanent and transient ischemia models in mice as measured by functional outcome and lesion size. Copper delivery in the ischemic brains modulates the inflammatory response, specifically affecting the myeloid cells. It reduces CD45 and Iba1 immunoreactivity, and alters the morphology of Iba1 positive cells in the ischemic brain. CuII(atsm) also protects endogenous microglia against ischemic insult and reduces the proportion of invading monocytes. These results demonstrate that the copper complex CuII(atsm) is an inflammation-modulating compound with high therapeutic potential in stroke and is a strong candidate for the development of therapies for acute brain injury.
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko T
authors.initials: MT
authors.lastname: Huuskonen
authors.affiliation: Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Qing-Zhang
authors.initials: QZ
authors.lastname: Tuo
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Loppi
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Hiramani
authors.initials: H
authors.lastname: Dhungana
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Korhonen
authors.affiliation: School of Chemistry and Bio21 Institute for Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Lachlan E
authors.initials: LE
authors.lastname: McInnes
authors.affiliation: School of Chemistry and Bio21 Institute for Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sara
authors.initials: S
authors.lastname: Wojciechowski
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lejavova
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Pomeshchik
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Periviita
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Kosonen
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Martina
authors.initials: M
authors.lastname: Giordano
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Walker
authors.affiliation: Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. tony.white@qimrberghofer.edu.au.|Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. tony.white@qimrberghofer.edu.au.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. tony.white@qimrberghofer.edu.au.|Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Locked Bag 2000, Herston, QLD, 4029, Australia. tony.white@qimrberghofer.edu.au.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. peng.lei@scu.edu.cn.|Department of Neurology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. peng.lei@scu.edu.cn.|Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China. peng.lei@scu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Lei
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. katja.kanninen@uef.fi.
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism* / Q000517:prevention & control; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009942:Organometallic Compounds / Q000008:administration & dosage*; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control; D013882:Thiosemicarbazones / Q000008:administration & dosage*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D056831:Coordination Complexes; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: CuII(atsm); Microglia; Neuroinflammation; Neuron; Stroke