Nada Shadia E, Tulsulkar Jatin, Shah Zahoor A
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Avenue, Toledo, OH, 43614, USA.
Mol Neurobiol. 2014 Apr;49(2):945-56. doi: 10.1007/s12035-013-8572-x. Epub 2013 Oct 24.
Stroke is the fourth leading cause of death and a major cause of disability in stroke survivors. Studies have underlined the importance of repair mechanisms in the recovery phase of stroke. Neurogenesis in response to brain injury is one of the regeneration processes that, if enhanced, may offer better stroke treatment alternatives. Previously, we have demonstrated antioxidant, neuritogenic, and angiogenic properties of Ginkgo biloba/EGb 761® (EGb 761) in different mouse models of stroke. In the present study, we were interested to study whether EGb 761 could protect mice from permanent middle cerebral artery occlusion (pMCAO) and enhance neurogenesis. EGb 761 pre- and posttreated mice had lower infarct volume and improved motor skills with enhanced proliferation of neuronal stem/progenitor cells (NSPCs) at 24 h and 7 days posttreatment. Netrin-1 and its receptors (DCC and UNC5B) that mediate axonal attraction and repulsion were observed to be overexpressed in NSPCs only, implying that netrin-1 and its receptors might have partly played a role in enhanced neurogenesis. Interestingly, in heme oxygenase 1 knockout mice (HO1(-/-)), neurogenesis was significantly lower than in vehicle-treated mice at day 8. Furthermore, EGb 761 posttreated mice also demonstrated heme oxygenase 1 (HO1)-activated pathway of phosphorylated glycogen synthase kinase 3 α/β (p-GSK-3 α/β), collapsin response mediator protein 2 (CRMP-2), semaphorin3A (SEMA3A), and Wnt, suggesting probable signaling pathways involved in proliferation, differentiation, and migration of NSPCs. Together, these results propose that EGb 761 not only has antioxidant, neuritogenic, and angiogenic properties, but can also augment the repair and regeneration mechanisms following stroke.
中风是第四大主要死因，也是中风幸存者残疾的主要原因。研究强调了修复机制在中风恢复阶段的重要性。响应脑损伤的神经发生是一种再生过程，如果得到增强，可能会提供更好的中风治疗选择。此前，我们已在不同的中风小鼠模型中证明了银杏叶提取物/EGb 761®（EGb 761）的抗氧化、促神经突生长和血管生成特性。在本研究中，我们感兴趣的是研究EGb 761是否能保护小鼠免受永久性大脑中动脉闭塞（pMCAO）的影响并增强神经发生。EGb 761预处理和后处理的小鼠梗死体积较小，运动技能得到改善，在治疗后24小时和7天时神经元干/祖细胞（NSPCs）的增殖增强。观察到仅在NSPCs中过表达介导轴突吸引和排斥的Netrin-1及其受体（DCC和UNC5B），这意味着Netrin-1及其受体可能在增强神经发生中部分发挥了作用。有趣的是，在血红素加氧酶1基因敲除小鼠（HO1(-/-)）中，第8天时神经发生明显低于用载体处理的小鼠。此外，EGb 761后处理的小鼠还表现出血红素加氧酶1（HO1）激活的磷酸化糖原合酶激酶3α/β（p-GSK-3α/β）、塌陷反应介导蛋白2（CRMP-2）、信号素3A（SEMA3A）和Wnt信号通路，提示可能参与NSPCs增殖、分化和迁移的信号通路。总之，这些结果表明EGb 761不仅具有抗氧化、促神经突生长和血管生成特性，还能增强中风后的修复和再生机制。
