Post-ischemic Administration of Heparin-Binding Epidermal Growth Factor-like Growth Factor (HB-EGF) Reduces Infarct Size and Modifies Neurogenesis after Focal Cerebral Ischemia in the Rat

Kunlin Jin, Yunjuan Sun, Lin Xie, Jocelyn Childs, Xiao Ou Mao, David A. Greenberg

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia-inducible, neuroprotective protein that also stimulates proliferation of neuronal precursor cells. Accordingly, HB-EGF may contribute to recovery from cerebral injury through direct neuroprotective effects, by enhancing neurogenesis, or both. When administered by the intracerebroventricular route 1-3 days after focal cerebral ischemia in adult rats, HB-EGF decreased the volume of the resulting infarcts and reduced post-ischemic neurological deficits. HB-EGF also increased the incorporation of bromodeoxy-uridine into cells expressing the immature neuronaI neuronal marker protein TUC-4 in the dentate subgranular and rostral subventricular zones, consistent with increased proliferation of neuronal precursors. However, HB-EGF decreased the number of newborn neurons that migrated into the ischemic striatum, perhaps partly because reduction of infarct size by HB-EGF also reduced the stimulus to migration. To determine if HB-EGF might also directly inhibit migration of neuronal precursors, we co-cultured subventricular zone (SVZ) explants treated with HB-EGF or vehicle together with hypoxic cerebral cortical explants, and measured cell migration from the former toward the latter. HB-EGF reduced directed migration of SVZ cells toward the cortical explants, possibly due to a local chemoattractant effect on neuronal precursor cells, which may be mediated through the HB-EGF-specific receptor, N-arginine dibasic convertase. The delayed neuroprotective effect of HB-EGF may have implications for efforts to prolong the therapeutic window for intervention in stroke.

Original languageEnglish
Pages (from-to)399-408
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume24
Issue number4
DOIs
StatePublished - Apr 2004

Keywords

  • HB-EGF
  • Infarct
  • Ischemia
  • Neurogenesis
  • Regeneration
  • Stroke

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