DOI: 10.1007/s13311-016-0504-9 Pages: 1-14
Article Type: Original Article

The Copper bis(thiosemicarbazone) Complex CuII(atsm) Is Protective Against Cerebral Ischemia Through Modulation of the Inflammatory Milieu

1. University of Eastern Finland, Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences

2. Huazhong University of Science and Technology, Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College

3. The University of Melbourne, Florey Institute of Neuroscience and Mental Health

4. The University of Melbourne, School of Chemistry and Bio21 Institute for Molecular Science and Biotechnology

5. The University of Melbourne, Department of Pathology

6. University of Newcastle, School of Biomedical Sciences and Pharmacy

7. QIMR Berghofer Medical Research Institute

8. Royal Brisbane Hospital, Cell and Molecular Biology, QIMR Berghofer Medical Research Institute

9. Sichuan University, Department of Neurology, State Key Laboratory of Biotherapy, West China Hospital

10. Collaborative Innovation Center for Biotherapy

Correspondence to:
Katja M. Kanninen
Tel: +358-40-1354377
Email: katja.kanninen@uef.fi

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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.

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  • Online: Jan 3, 2017

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