Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice

Qian Li, Jieru Wan, Xi Lan, Xiaoning Han, Zhongyu Wang, Jian Wang

Research output: Contribution to journalArticle

Abstract

Iron overload plays a key role in the secondary brain damage that develops after intracerebral hemorrhage (ICH). The significant increase in iron deposition is associated with the generation of reactive oxygen species (ROS), which leads to oxidative brain damage. In this study, we examined the protective effects of VK-28, a brain-permeable iron chelator, against hemoglobin toxicity in an ex vivo organotypic hippocampal slice culture (OHSC) model and in middle-aged mice subjected to an in vivo, collagenase-induced ICH model. We found that the effects of VK-28 were similar to those of deferoxamine (DFX), a well-studied iron chelator. Both decreased cell death and ROS production in OHSCs and in vivo, decreased iron-deposition and microglial activation around hematoma in vivo, and improved neurologic function. Moreover, compared with DFX, VK-28 polarized microglia to an M2-like phenotype, reduced brain water content, deceased white matter injury, improved neurobehavioral performance, and reduced overall death rate after ICH. The protection of VK-28 was confirmed in a blood-injection ICH model and in aged-male and young female mice. Our findings indicate that VK-28 is protective against iron toxicity after ICH and that, at the dosage tested, it has better efficacy and less toxicity than DFX does.

Original languageEnglish (US)
Pages (from-to)3110-3123
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

    Fingerprint

Keywords

  • Deferoxamine
  • intracerebral hemorrhage
  • iron chelator
  • microglial polarization
  • neurolucida

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this