Neurotherapeutics

, Volume 14, Issue 2, pp 519–532 | Cite as

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

  • Mikko T. Huuskonen
  • Qing-zhang Tuo
  • Sanna Loppi
  • Hiramani Dhungana
  • Paula Korhonen
  • Lachlan E. McInnes
  • Paul S. Donnelly
  • Alexandra Grubman
  • Sara Wojciechowski
  • Katarina Lejavova
  • Yuriy Pomeshchik
  • Laura Periviita
  • Lotta Kosonen
  • Martina Giordano
  • Frederick R. Walker
  • Rong Liu
  • Ashley I. Bush
  • Jari Koistinaho
  • Tarja Malm
  • Anthony R. White
  • Peng Lei
  • Katja M. Kanninen
Original Article

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.

Key Words

CuII(atsm) Stroke Microglia Neuron Neuroinflammation 

Supplementary material

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2016

Authors and Affiliations

  • Mikko T. Huuskonen
    • 1
  • Qing-zhang Tuo
    • 2
    • 3
  • Sanna Loppi
    • 1
  • Hiramani Dhungana
    • 1
  • Paula Korhonen
    • 1
  • Lachlan E. McInnes
    • 4
  • Paul S. Donnelly
    • 4
  • Alexandra Grubman
    • 5
  • Sara Wojciechowski
    • 1
  • Katarina Lejavova
    • 1
  • Yuriy Pomeshchik
    • 1
  • Laura Periviita
    • 1
  • Lotta Kosonen
    • 1
  • Martina Giordano
    • 1
  • Frederick R. Walker
    • 6
  • Rong Liu
    • 2
  • Ashley I. Bush
    • 3
  • Jari Koistinaho
    • 1
  • Tarja Malm
    • 1
  • Anthony R. White
    • 3
    • 5
    • 7
    • 8
  • Peng Lei
    • 3
    • 9
    • 10
  • Katja M. Kanninen
    • 1
  1. 1.Department of Neurobiology, A.I.Virtanen Institute for Molecular SciencesUniversity of Eastern FinlandKuopioFinland
  2. 2.Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  4. 4.School of Chemistry and Bio21 Institute for Molecular Science and BiotechnologyThe University of MelbourneParkvilleAustralia
  5. 5.Department of PathologyThe University of MelbourneParkvilleAustralia
  6. 6.School of Biomedical Sciences and PharmacyUniversity of NewcastleCallaghanAustralia
  7. 7.QIMR Berghofer Medical Research InstituteHerstonAustralia
  8. 8.Cell and Molecular Biology, QIMR Berghofer Medical Research InstituteRoyal Brisbane HospitalHerstonAustralia
  9. 9.Department of Neurology, State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
  10. 10.Collaborative Innovation Center for BiotherapyChengduChina

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