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
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
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DOI：
10.1097/00004647-200404000-00005
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发表时间：
2004-04-01
影响因子：
6.3
通讯作者：
Greenberg, DA
中科院分区：
文献类型：
--
作者：
Jin, KL;Sun, YJ;Greenberg, DA
肝素结合表皮生长因子样生长因子（HB-EGF）是一种缺氧诱导的神经保护蛋白，也刺激神经元前体细胞的增殖。因此，HB-EGF可能通过直接的神经保护作用，通过增强神经发生或两者兼而有之来促进脑损伤的恢复。当在成年大鼠局灶性脑缺血后1-3天通过侧脑室途径给药时，HB-EGF减少了所导致的梗死体积并减少了缺血后神经功能缺损。HB-EGF还增加了溴脱氧尿苷掺入表达未成熟神经元标记蛋白TUC-4的细胞中的齿状颗粒下和喙侧脑室下区，与神经元前体细胞增殖增加一致。然而，HB-EGF减少了迁移到缺血纹状体的新生神经元的数量，可能部分原因是HB-EGF减少了梗死面积也减少了迁移的刺激。为了确定HB-EGF是否也可能直接抑制神经元前体细胞的迁移，我们将用HB-EGF或载剂处理的室管膜下区（SVZ）外植体与缺氧的大脑皮层外植体一起共培养，并测量从前者向后者的细胞迁移。HB-EGF减少了SVZ细胞向皮质外植体的定向迁移，这可能是由于对神经元前体细胞的局部趋化作用，这可能是通过HB-EGF特异性受体N-精氨酸二元转化酶介导的。HB-EGF的延迟神经保护作用可能对延长中风干预治疗窗口的努力有影响。
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 bromodeoxyuridine into cells expressing the immature 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.