Poststroke Sonic Hedgehog Agonist Treatment Improves Functional Recovery by Enhancing Neurogenesis and Angiogenesis.
Poststroke Sonic Hedgehog Agonist Treatment Improves Functional Recovery by Enhancing Neurogenesis and Angiogenesis.
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DOI：
10.1161/strokeaha.117.016650
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发表时间：
2017-06
期刊：
影响因子：
8.3
通讯作者：
Luo Y
中科院分区：
文献类型：
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作者：
Jin Y;Barnett A;Zhang Y;Yu X;Luo Y
由于rtPA（重组组织型纤溶酶原激活剂）治疗窗的限制，需要开发延迟治疗脑卒中的方法。在这项研究中，我们研究了延迟卒中后治疗（3-8天后）的音刺猬通路激动剂（SAG）对功能恢复的疗效和潜在机制。我们在中风后1个月使用运动分析和巴恩斯迷宫测试来评估功能恢复。我们利用遗传诱导的神经干细胞特异性报告小鼠系（nestin-CreERT 2-R26 R-YFP）来标记和跟踪它们在缺血脑中的增殖、存活和分化。采用MRI技术和免疫组化染色评价脑组织损伤、血管生成和脑血流恢复。我们的研究结果表明，延迟治疗中风小鼠的SAG结果在中风后一个月的运动功能和认知功能的功能恢复增强。此外，利用nestincreERT 2-YFP小鼠，我们表明中风后SAG治疗增加了缺血脑中源自SVZ和SGZ神经干细胞（NSC）的存活新生细胞、总存活DCX+（Doublecortin）成神经细胞和神经元（NeuN+/YFP+）。SAG治疗还改善了缺血区域的脑组织修复，这得到了我们的T2加权MRI、通过动脉自旋标记（ASL）的脑血流（CBF）图和免疫组织化学（α-平滑肌肌动蛋白和CD 31免疫染色）的支持。这些数据证实了hedgehog通路在卒中后脑修复和功能恢复中的重要作用，提示了延长卒中后调节shh通路的潜在治疗策略的治疗窗。
Due to the limitation in treatment window of the rtPA (recombinant tissue plasminogen activator), the development of delayed treatment for stroke is needed. In this study, we examined the efficacy of delayed post-stroke treatment (post 3–8 days) of the sonic hedgehog pathway agonist (SAG) on functional recovery and the underlying mechanisms. We evaluated functional recovery at 1 month after stroke using locomotion analysis and Barnes maze test for cognitive function. We utilized a genetically inducible NSC-specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track their proliferation, survival and differentiation in ischemic brain. Brain tissue damage, angiogenesis and cerebral blood flow recovery was evaluated using MRI techniques and immunostaining. Our results show that delayed treatment of SAG in stroke mice results in enhanced functional recovery both in locomotor function and cognitive function at one month after stroke. Further, utilizing the nestincreERT2-YFP mice, we showed that post-stroke SAG treatment increased surviving newly born cells derived from both SVZ and SGZ neural stem cells (NSCs), total surviving DCX+ (Doublecortin) neuroblast cells and neurons (NeuN+/YFP+) in the ischemic brain. SAG treatment also improved the brain tissue repair in ischemic region supported by our T2 weighted MRI, Cerebral Blood Flow (CBF) map by Arterial-Spin-Labeling (ASL) and immunohistochemistry (alpha-smooth muscle actin and CD31 immunostaining). These data confirm an important role for the hedgehog pathway in post-stroke brain repair and functional recovery, suggesting a prolonged treatment window for potential treatment strategy to modulate shh pathway after stroke.