经血管移植神经干细胞治疗放射诱导认知功能障碍机制研究

Irradaition-induced cognitive dysfunction is one of the most important clinical issues for brain tumor , there is no effective treatment by now. Our preliminary studies showed that blood-brain barrier of rat would be destroyed and adhesion molecule would be upregulated after cranial irradiation. We assume that neural stem cells transplanted by vascular way would enter into brain parenchyma through the destroyed blood-brain barrier, and these grafted stem cells could ameliorate irradiation-induced cognitive dysfunction by derict substitute or addition of endogenous neurogenesis. To test this hypothesis, we would observe: (1) the nerual stem cells transplanted by vascular way could enter into brain parenchyma and the positional relationship between these stem cells and endothelial cells; (2)neural stem cells entering into brain parenchyma would be affected by inhibition of endothelial cells apoptosis or adhesion molecule upregulation; (3)spatial memory of rat could be rescued by neural stem cells transplantation;(4)grafted neural stem cells would affect endogenous neurogenesis、signaling molecules of administering neurogenesis and neuroinflammation; function of astrocytes originated from grafted neural stem cells. This issue is very important for theory and practice, which will clarify the mechanisms of grafted neural stem cells entering into brain parenchyma and ameliorating irradiation-induced cognitive dysfunction.

放射诱导的认知功能障碍是脑部肿瘤放射治疗最重要的临床问题之一，目前尚无有效的治疗方法。近年来的研究发现经颅骨移植神经干细胞能够解救放射诱导的认知功能障碍，而经血管移植神经干细胞尚未见研究。我们的前期实验发现，大鼠脑部照射后血脑屏障开放，粘附分子表达增加。因此我们假设经血管移植的神经干细胞能通过这种开放的血脑屏障进入脑实质并增加内源性神经发生，治疗放射诱导的认知功能障碍。为验证此假设，我们将：（1）观测经血管移植的神经干细胞是否进入脑实质；（2）观测抑制内皮细胞凋亡、封闭粘附分子表达对神经干细胞进入脑实质的影响以明确其进入脑实质的机制；（3）明确经血管移植神经干细胞对大鼠脑部照射后学习记忆能力的改善作用；（4）观察神经干细胞移植对内源性神经发生的影响。本课题将阐明脑部照射后经血管移植神经干细胞进入脑实质及治疗放射诱导认知功能障碍的机制，具有重要理论及实践意义。

放疗是各类脑肿瘤的重要治疗方法，但会导致一定的神经毒性，其中放射性认知功能障碍的发生率较高，严重影响患者的生活质量。海马神经发生减少是放射性认知功能障碍的重要原因。神经干细胞移植可以有效缓解放射性认知功能障碍，但其机制尚不清楚。我们的研究发现，脑部照射后海马齿状回仍然有大量神经干细胞存在，较对照组无显著性差异，表明脑部照射后神经干细胞数量不是放射性认知功能障碍的关键问题。神经干细胞移植不是为了补充干细胞池，而是通过释放微泡抑制小胶质细胞过度活化从而改善原住神经干细胞巢的微环境。我们发现，大鼠脑部放疗后血脑屏障破坏、毛细胞血管减少、小胶质细胞过度活化均参与神经干细胞巢的微环境改变。我们进一步发现，在大鼠脑部放疗后给予电针治疗能改善神经干细胞微环境：保护血脑屏障、抑制小胶质细胞活化、降低炎症因子表达、降低兴奋性神经递质谷氨酸受体的表达、增加脑源性神经因子含量，从而提高海马神经发生水平，缓解大鼠脑部照射后的学习记忆能力损伤。本课题的开展拓宽了对放射性认知功能障碍的机制的认识，提出了放射性认知功能障碍的防治重点——改善神经干细胞的微环境，并探索出电针这种简便易行的疗法，为临床转化奠定了理论基础。