The role of neutrophils in mediating stroke injury in the diabetic db/db mouse brain following hypoxia-ischemia

Rashmi Kumari, Kerstin Bettermann, Lisa Willing, Kusum Sinha, Ian A. Simpson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Diabetic mice exhibit increased mortality and morbidity following stroke. Recent studies from our laboratory have indicated that increased morbidity in diabetic db/db mice relative to their non-diabetic db/+ littermates is associated with increased levels of MMP-9 protease activity, increased blood-brain barrier (BBB) permeability, and greater neutrophil infiltration following hypoxic/ischemic (H/I) insult. Neutrophils are a major source of proteases and reactive oxygen species and studies have reported neutrophil depletion/inhibition is protective in certain models of experimental stroke. The objective of the current study is to determine the role of neutrophils in the increased morbidity seen in db/db mice following acute ischemic stroke. In this study, we found a significant increase in circulating neutrophils in the db/db mice at 4 h post H/I, which bound to endothelial cells in the ipsilateral hemisphere and infiltrated into brain tissue by 24 h of recovery. Depletion of circulating neutrophils resulted in reduced neutrophil concentrations in blood and in the ipsilateral hemispheres of the brain of both db/+ and db/db mice and decreased the levels of MMP-9 within the infarcted area. This resulted in smaller infarct size in the db/db mice compared to non-treated controls but did not affect stroke outcome in db/+ mice. While there was a significant correlation between neutrophil number and the levels of MMP-9 in the ipsilateral hemisphere of control and diabetic mice, surprisingly, neutrophil depletion had no effect on BBB permeability in either group. Thus, the current study suggests that neutrophil depletion reduces MMP-9 protease levels and improves stroke outcome in db/db mice but not in their db/+ counterparts.

Original languageEnglish (US)
Article number104790
JournalNeurochemistry International
Volume139
DOIs
StatePublished - Oct 2020

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cell Biology

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