Wang Feng, Wu Hongwei, Hu Azhen, Dong Lei, Lin Xiaoxia, Li Menghao, Wang Yongling, Li Wenjun, Chang Liansheng, Chang Yuqiao, Liu Hanqing, Shi Yu, Li Nana
Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China.
Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, China.
Front Bioeng Biotechnol. 2022 Aug 15;10:961728. doi: 10.3389/fbioe.2022.961728. eCollection 2022.
Drug addiction is a serious problem globally, recently exacerbated by the COVID-19 pandemic. Glial cell-derived neurotrophic factor (GDNF) is considered a potentially effective strategy for the treatment of addiction. Previous animal experiments have proven that GDNF has a good therapeutic effect on drug addiction, but its clinical application is limited due to its poor blood-brain barrier (BBB) permeability. Low-frequency focused ultrasound, combined with microbubbles, is a non-invasive and reversible technique for locally-targeted BBB opening. In the present study, magnetic resonance imaging-guided low-frequency focused ultrasound, combined with GDNF microbubbles, was used to target BBB opening in the ventral tegmental area (VTA) region. The effects of GDNF on morphine-induced conditioned place preference (CPP) and acute withdrawal symptoms in rats after a partially opened BBB were evaluated by behavioral observation. Western blot was used to detect changes in tyrosine hydroxylase (TH) expression levels in the VTA region after different treatments, and high performance liquid chromatography was used to detect the changes in monoamine neurotransmitter content. The results showed that ultrasound combined with GDNF microbubbles targeted and opened the BBB in the VTA region, and significantly increased GDNF content, destroyed morphine-induced CPP, and reduced the withdrawal symptoms of morphine addiction in rats. Furthermore, the up-regulation of TH expression and the increase of norepinephrine and dopamine content induced by morphine were significantly reversed, and the increase of 5-hydroxytryptamine content was partially reversed. Therefore, ultrasound combined with GDNF microbubbles to target and open the BBB can effectively increase the content of central GDNF, thus playing a therapeutic role in morphine addiction. Our study provides a new approach to locally open the BBB and target delivery of neurotrophic factors, such as GDNF, to treat brain diseases like addiction.
药物成瘾是一个全球性的严重问题，最近因新冠疫情而加剧。胶质细胞源性神经营养因子（GDNF）被认为是治疗成瘾的一种潜在有效策略。以往的动物实验证明，GDNF对药物成瘾有良好的治疗效果，但其临床应用因血脑屏障（BBB）通透性差而受到限制。低频聚焦超声联合微泡是一种用于局部靶向打开血脑屏障的非侵入性且可逆的技术。在本研究中，磁共振成像引导的低频聚焦超声联合GDNF微泡被用于靶向打开腹侧被盖区（VTA）区域的血脑屏障。通过行为观察评估了部分打开血脑屏障后GDNF对大鼠吗啡诱导的条件性位置偏爱（CPP）和急性戒断症状的影响。采用蛋白质免疫印迹法检测不同处理后VTA区域酪氨酸羟化酶（TH）表达水平的变化，采用高效液相色谱法检测单胺类神经递质含量的变化。结果表明，超声联合GDNF微泡靶向打开了VTA区域的血脑屏障，显著增加了GDNF含量，破坏了吗啡诱导的CPP，并减轻了大鼠吗啡成瘾的戒断症状。此外，吗啡诱导的TH表达上调以及去甲肾上腺素和多巴胺含量的增加被显著逆转，5-羟色胺含量的增加被部分逆转。因此超声联合GDNF微泡靶向打开血脑屏障可有效增加中枢GDNF含量，从而对吗啡成瘾发挥治疗作用。我们的研究为局部打开血脑屏障以及靶向递送神经营养因子（如GDNF）以治疗成瘾等脑部疾病提供了一种新方法。
