Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation

作者：Doeppner Thorsten R^*; Kaltwasser Britta; ElAli Ayman; Zechariah Anil; Hermann Dirk M; Baehr Mathias

来源：Journal of Cerebral Blood Flow and Metabolism, 2011, 31(5): 1251-1262.

DOI：10.1038/jcbfm.2010.211

• cerebral ischemia
• hepatocyte growth factor
• matrix metalloproteases
• neural precursor cells
• neurogenesis
• stroke

Hepatocyte growth factor (HGF) is an interesting candidate for acute stroke treatment as shown by continuous infusion or gene delivery protocols. However, little is known about HGF-mediated long-term effects. The present study therefore analyzed long-term effects of an acute intrastriatal HGF treatment (5 mu g) after a 45-minute stroke, with regard to brain injury and neurologic recovery. Hepatocyte growth factor induced long-term neuroprotection as assessed by infarct volume and neuronal cell death analysis for as long as 4 weeks after stroke, which was associated with sustained neurologic recovery as evidenced by corner-turn and tight-rope tests. Analyzing underlying mechanisms of HGF-induced sustained neuroprotection, enhanced cell proliferation followed by increased neuronal differentiation of neural precursor cells (NPCs) was observed in the ischemic striatum of HGF-treated mice, which persisted for up to 4 weeks. In line with this, HGF promoted neurosphere formation as well as proliferation of NPC and decreased caspase-3-dependent hypoxic injury in vitro. Preservation of blood-brain barrier integrity 24 hours after stroke was furthermore noticed in animals receiving HGF, which was associated with the inhibition of matrix metalloproteases (MMP)-2 and MMP-9 at 4 and 24 hours, respectively. We suggest that sustained recruitment of proliferating cells together with improved neurovascular remodeling provides an explanation for HGF-induced long-term neuroprotection. Journal of Cerebral Blood Flow & Metabolism(2011) 31, 1251-1262; doi:10.1038/jcbfm.2010.211; published online 1 December 2010

• 出版日期2011-5