Glial cell line derived neurotropic factor (GDNF) plays a crucial role in the development and maintenance of glial cells, serotonergic and dopaminergic neurons. A positively therapeutic effect has been demonstrated on some animal neurodegenerative diseases. However, the inability to deliver the protein across blood brain barrier (BBB) into damaged brain region limits its clinical application. Here, we developed GDNF-loaded microbubbles (MBs) and achieved a local and precise delivery of GDNF into the brain through MRI-guided focused ultrasound-induced BBB disruption. To demonstrate the therapeutic effect, rat depression model was developed by chronic mild stress treatment. Typical depression behaviors were confirmed. MRI-guided focused ultrasound was used to irradiate the GDNF-loaded MBs. Obvious BBB opening was observed in the treated rat brains and a significant higher GDNF concentration was detected in the ultrasound-treated brain tissues. Behavioral tests demonstrated the increased GDNF could reverse the depressive-like behaviors induced by chronic mild stress, improve the expression of 5-HT 1B receptor and the protein p11, and increase the number of 5-HT or TPH2 immunoreactive neurons. In conclusion, our study provided an effective approach to deliver GDNF proteins into brain to treat rat depression through MRI-guided focused ultrasound-induced destruction of blood-brain barrier.

中文翻译：

---

MRI引导的聚焦超声诱导的血脑屏障破坏，以将胶质细胞系衍生的神经营养因子蛋白递送到大脑中，以治疗大鼠抑郁症。

胶质细胞系衍生的神经营养因子（GDNF）在神经胶质细胞，血清素能和多巴胺能神经元的发育和维持中起着至关重要的作用。已经证明对某些动物神经退行性疾病具有积极的治疗作用。但是，无法将蛋白跨血脑屏障（BBB）输送到受损的大脑区域限制了其临床应用。在这里，我们开发了装载GDNF的微泡（MBs），并通过MRI引导的聚焦超声引起的BBB破坏，将GDNF局部准确地递送到大脑中。为了证明治疗效果，通过慢性轻度应激治疗建立了大鼠抑郁模型。证实了典型的抑郁行为。MRI引导的聚焦超声被用来照射GDNF加载的MB。在处理过的大鼠大脑中观察到明显的血脑屏障开放，在超声处理过的脑组织中检测到明显更高的GDNF浓度。行为测试表明，增加的GDNF可以逆转慢性轻度应激引起的抑郁样行为，改善5-HT 1B受体和p11蛋白的表达，并增加5-HT或TPH2免疫反应神经元的数量。总之，我们的研究提供了一种有效的方法，通过MRI引导的聚焦超声诱导的血脑屏障破坏，将GDNF蛋白输送到大脑中以治疗大鼠抑郁症。改善5-HT 1B受体和蛋白p11的表达，并增加5-HT或TPH2免疫反应性神经元的数量。总之，我们的研究提供了一种有效的方法，通过MRI引导的聚焦超声诱导的血脑屏障破坏，将GDNF蛋白输送到大脑中以治疗大鼠抑郁症。改善5-HT 1B受体和蛋白p11的表达，并增加5-HT或TPH2免疫反应性神经元的数量。总之，我们的研究提供了一种有效的方法，通过MRI引导的聚焦超声诱导的血脑屏障破坏，将GDNF蛋白输送到大脑中以治疗大鼠抑郁症。