Impaired wound healing after cerebral hypoxia-ischemia in the diabetic mouse

Rashmi Kumari, Lisa B. Willing, J. Kyle Krady, Susan J. Vannucci, Ian A. Simpson

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Impaired peripheral wound healing is a hallmark of diabetis pathology and has been attributed to compromised macrophage activation. Stroke is another component of diabetic pathology, with increased tissue infarction and worsened recovery although the mechanisms remain unresolved. In this study, we investigated whether a compromised glial/macrophage response might contribute to cerebral hypoxic-ischemic (H/I) brain damage in diabetic (db/db), relative to their normoglycemic db/+ mice. Hypoxia-ischemia was induced in 8-week-old male db/db and db/+ mice by the ligation of right common carotid artery followed by systemic hypoxia (8% O2: 92% N2) for 17 mins. Mice were killed at specific intervals of reperfusion/recovery and the brains analyzed by in situ hybridization or total RNA isolation. In situ hybridization using bfl-1 (microglia) and glial fibrillary acidic protein (GFAP) (astrocytes) revealed expression of both bfl-1 and GFAP in the ipsilateral hemisphere at 4 h in the db/+ mice, which was delayed and minimal in the db/db mice. RNase protection assays showed a robust increase in expression of the proinflamatory cytokines tumor necrosis factor-α (TNFα), interleukin-1 IL-1α, and IL-1β mRNA in the db/+ mice at 6 to 8 h of reperfusion peaking at 8 to 12 h; in db/db mice expression was markedly delayed and diminished. Real-time-polymerase chain reaction (RT-PCR) confirmed the reduced and delayed expression TNFα, IL-1α, IL-1β, and the growth factors insulin-like growth factor-1 and ciliary neurotrophic factor in the db/db mice; enzyme-linked immunosorbent assays confirmed the reduced and delayed translation of IL-1β protein. These findings suggest that a compromised inflammatory response may underlie the greater infarct associated with diabetic db/db mice compared with their nondiabetic littermates following a hypoxic/ischemic insult.

Original languageEnglish (US)
Pages (from-to)710-718
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number4
DOIs
StatePublished - Apr 26 2007

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All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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