Hillenbrand Matthias, Holzbach Thomas, Matiasek Kaspar, Schlegel Jürgen, Giunta Riccardo E
Neurol Res. 2015 Mar;37(3):197-203. doi: 10.1179/1743132814Y.0000000441. Epub 2014 Sep 12.
The treatment of obstetric brachial plexus palsy has been limited to conservative therapies and surgical reconstruction of peripheral nerves. In addition to the damage of the brachial plexus itself, it also leads to a loss of the corresponding motoneurons in the spinal cord, which raises the need for supportive strategies that take the participation of the central nervous system into account. Based on the protective and regenerative effects of VEGF on neural tissue, our aim was to analyse the effect on nerve regeneration by adenoviral gene transfer of vascular endothelial growth factor (VEGF) in postpartum nerve injury of the brachial plexus in rats. In the present study, we induced a selective crush injury to the left spinal roots C5 and C6 in 18 rats within 24 hours after birth and examined the effect of VEGF-gene therapy on nerve regeneration. For gene transduction an adenoviral vector encoding for VEGF165 (AdCMV.VEGF165) was used. In a period of 11 weeks, starting 3 weeks post-operatively, functional regeneration was assessed weekly by behavioural analysis and force measurement of the upper limb. Morphometric evaluation was carried out 8 months post-operatively and consisted of a histological examination of the deltoid muscle and the brachial plexus according to defined criteria of degeneration. In addition, atrophy of the deltoid muscle was evaluated by weight determination comparing the left with the right side. VEGF expression in the brachial plexus was quantified by an enzyme-linked immunosorbent assay (ELISA). Furthermore the motoneurons of the spinal cord segment C5 were counted comparing the left with the right side. On the functional level, VEGF-treated animals showed faster nerve regeneration. It was found less degeneration and smaller mass reduction of the deltoid muscle in VEGF-treated animals. We observed significantly less degeneration of the brachial plexus and a greater number of surviving motoneurons (P < 0·05) in the VEGF group. The results of this study confirmed the positive effect of VEGF-gene therapy on regeneration and survival of nerve cells. We could demonstrate a significant improvement on the motor-functional as well as on the histomorphological level. However, increased vascularization of the nerve tissue caused by VEGF does not seem to be the major reason for these effects. The clinical use of adenoviral VEGF-gene therapy in the newborn cannot be justified so far.
产科臂丛神经麻痹的治疗一直局限于保守治疗和外周神经的外科重建。除了臂丛神经本身的损伤外，它还会导致脊髓中相应运动神经元的丧失，这就需要考虑中枢神经系统参与的支持性策略。基于血管内皮生长因子（VEGF）对神经组织的保护和再生作用，我们的目的是分析血管内皮生长因子（VEGF）腺病毒基因转移对大鼠产后臂丛神经损伤神经再生的影响。在本研究中，我们在18只大鼠出生后24小时内对其左侧C5和C6脊髓神经根进行选择性挤压损伤，并研究VEGF基因治疗对神经再生的影响。基因转导使用编码VEGF165的腺病毒载体（AdCMV.VEGF165）。术后3周开始的11周内，每周通过行为分析和上肢力量测量对功能再生进行评估。术后8个月进行形态计量学评估，包括根据明确的变性标准对三角肌和臂丛神经进行组织学检查。此外，通过比较左右两侧的重量来评估三角肌的萎缩情况。通过酶联免疫吸附测定（ELISA）对臂丛神经中的VEGF表达进行定量。此外，比较左右两侧对C5脊髓节段的运动神经元进行计数。在功能水平上，接受VEGF治疗的动物神经再生更快。发现接受VEGF治疗的动物三角肌的变性较少且质量减轻较小。我们观察到VEGF组臂丛神经的变性明显较少，存活的运动神经元数量较多（P < 0·05）。本研究结果证实了VEGF基因治疗对神经细胞再生和存活的积极作用。我们可以证明在运动功能以及组织形态学水平上有显著改善。然而，VEGF引起的神经组织血管化增加似乎不是这些作用的主要原因。迄今为止，腺病毒VEGF基因治疗在新生儿中的临床应用尚无依据。
