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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro
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AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

机译：AAV-Syn-BDNF-EGFP病毒构建体在缺氧过程中对海马神经网络发挥神经保护作用

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Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood–brain barrier and the short half-life period, challenge the potential use of BDNF in clinical practice. Gene therapy could overcome these limitations. Investigating the influence of viral vectors on the neural network level is of particular interest because viral overexpression affects different aspects of cell metabolism and interactions between neurons. The present work aimed to investigate the influence of the adeno-associated virus (AAV)-Syn-BDNF-EGFP virus construct on neural network activity parameters in an acute hypobaric hypoxia model in vitro. Materials and methods. An adeno-associated virus vector carrying the BDNF gene was constructed using the following plasmids: AAV-Syn-EGFP, pDP5, DJvector, and pHelper. The developed virus vector was then tested on primary hippocampal cultures obtained from C57BL/6 mouse embryos (E18). Acute hypobaric hypoxia was induced on day 21 in vitro. Spontaneous bioelectrical and calcium activity of neural networks in primary cultures and viability tests were analysed during normoxia and during the posthypoxic period. Results. BDNF overexpression by AAV-Syn-BDNF-EGFP does not affect cell viability or the main parameters of spontaneous bioelectrical activity in normoxia. Application of the developed virus construct partially eliminates the negative hypoxic consequences by preserving cell viability and maintaining spontaneous bioelectrical activity in the cultures. Moreover, the internal functional structure, including the activation pattern of network bursts, the number of hubs, and the number of connections within network elements, is also partially preserved. BDNF overexpression prevents a decrease in the number of cells exhibiting calcium activity and maintains the frequency of calcium oscillations. Conclusion. This study revealed the pronounced antihypoxic and neuroprotective effects of AAV-Syn-BDNF-EGFP virus transduction in an acute normobaric hypoxia model.
机译：脑源性神经营养因子（BDNF）是关键信号分子之一，可在各种脑病理学中支持神经细胞的活力，可以被认为是一种潜在的治疗剂。但是，一些方法学上的困难，例如克服血脑屏障和半衰期短，对BDNF在临床实践中的潜在用途提出了挑战。基因疗法可以克服这些限制。研究病毒载体对神经网络水平的影响尤为重要，因为病毒过度表达会影响细胞代谢和神经元之间相互作用的不同方面。本工作旨在调查急性低压低氧模型中腺相关病毒（AAV）-Syn-BDNF-EGFP病毒构建体对神经网络活动参数的影响。材料和方法。使用以下质粒构建带有BDNF基因的腺相关病毒载体：AAV-Syn-EGFP，pDP5，DJvector和pHelper。然后在从C57BL / 6小鼠胚胎（E18）获得的海马原代培养物中测试了开发的病毒载体。体外第21天诱发了急性低压缺氧。在常氧和低氧后阶段，分析了原代培养物中神经网络的自发生物电和钙活性，并进行了活力测试。结果。 AAV-Syn-BDNF-EGFP引起的BDNF过表达不影响细胞生存力或正常氧中自发生物电活动的主要参数。通过保留细胞活力并在培养物中保持自发的生物电活性，开发的病毒构建体的应用可以部分消除负面的低氧后果。此外，还部分保留了内部功能结构，包括网络突发的激活模式，集线器的数量以及网元内的连接数量。 BDNF的过度表达可防止表现钙活性的细胞数量减少，并维持钙振荡的频率。结论。这项研究揭示了在急性常压低氧模型中，AAV-Syn-BDNF-EGFP病毒转导具有明显的抗缺氧和神经保护作用。

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