Ultrasound-targeted microbubble destruction (UTMD) in conjunction with neurotrophic factors (NFs) gene delivery has the potential to facilitate the penetration of therapeutic genes into the brain for neuroprotective therapy against neurodegenerative diseases. We previously presented a gene delivery system that conjugates gene-carrying liposomes with microbubbles (MBs) to open the blood-brain barrier (BBB) for the delivery of genes into the brain. Since both glia cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) can protect dopaminergic neurons from neurotoxicity demonstrated in Parkinson's disease (PD) animal models, the present study seeks (1) to develop a novel gene-nanocarrier MB complex carrying BDNF or GDNF gene and (2) to protect dopaminergic neurons in a mouse model of PD via the proposed UTMD system. In the experimental design, PD animals received treatment that delivered GDNF, BDNF, or combined GDNF/BDNF in conjunction with UTMD treatment, and pathological changes in dopamine neurons were histologically examined. Rotarod assay was employed to evaluate the motor behavior. Our results demonstrate that either BDNF or GDNF gene delivery via the UTMD system provides a neuroprotective effect with evidence of improvements of behavioral deficits, decreased calcium influx, GFAP and caspase 3 expression, and rescued dopaminergic neuronal loss. Simultaneously performing GDNF/BDNF gene delivery did not show additional benefits beyond individually delivering BDNF or GDNF genes, possibly due to a hampering effect of simultaneous GDNF/BDNF competing expressions, thus dampening the overall therapeutic effect. In conclusion, these results suggest that UTMD in conjunction with delivery of GDNF or BDNF gene can synergistically serve as an effective gene therapy strategy for neurodegenerative diseases.

中文翻译：

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载有超声反应的神经营养因子的微泡脂质体复合物：帕金森氏病治疗的临床前研究。

超声靶向微泡破坏（UTMD）结合神经营养因子（NFs）基因的传递具有促进治疗性基因渗透到大脑中的潜力，以进行针对神经退行性疾病的神经保护性治疗。我们先前提出了一种基因传递系统，该系统将携带基因的脂质体与微泡（MBs）结合在一起，以打开血脑屏障（BBB），将基因传递到大脑中。由于神经胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）都可以保护多巴胺能神经元免受帕金森氏病（PD）动物模型证明的神经毒性，本研究寻求（1）通过提出的UTMD系统开发携带BDNF或GDNF基因的新型基因-纳米载体MB复合物，以及（2）保护PD小鼠模型中的多巴胺能神经元。在实验设计中，PD动物接受了递送GDNF，BDNF或GDNF / BDNF联合UTMD处理的治疗，并组织学检查了多巴胺神经元的病理变化。使用Rotarod分析法评估运动行为。我们的结果表明，通过UTMD系统传递的BDNF或GDNF基因可提供神经保护作用，并具有改善行为缺陷，减少钙内流，GFAP和caspase 3表达以及挽救多巴胺能神经元丢失的证据。同时进行GDNF / BDNF基因递送并没有显示出超过单独递送BDNF或GDNF基因的额外好处，这可能是由于同时GDNF / BDNF竞争性表达的阻碍作用，从而削弱了总体治疗效果。总之，这些结果表明，UTMD与GDNF或BDNF基因的递送可以协同作用，作为神经退行性疾病的有效基因治疗策略。