Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
The Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford OX1 3RE, United Kingdom.
Neurobiol Dis. 2015 Feb;74:392-405. doi: 10.1016/j.nbd.2014.12.006. Epub 2014 Dec 19.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an accepted treatment for motor symptoms in a subset of Parkinson's disease (PD) patients. The mechanisms why DBS is effective are incompletely understood, but previous studies show that DBS targeted in brain structures other than the STN may modify the microvasculature. However, this has not been studied in PD subjects who have received STN-DBS. Here we investigated the extent and nature of microvascular changes in post-mortem STN samples from STN-DBS PD patients, compared to aged controls and PD patients who had not been treated with STN-DBS. We used immunohistochemical and immunofluorescent methods to assess serial STN-containing brain sections from PD and STN-DBS PD cases, compared to similar age controls using specific antibodies to detect capillaries, an adherens junction and tight junction-associated proteins as well as activated microglia. Cellular features in stained sections were quantified by confocal fluorescence microscopy and stereological methods in conjunction with in vitro imaging tools. We found significant upregulation of microvessel endothelial cell thickness, length and density but lowered activated microglia density and striking upregulation of all analysed adherens junction and tight junction-associated proteins in STN-DBS PD patients compared to non-DBS PD patients and controls. Moreover, in STN-DBS PD samples, expression of an angiogenic factor, vascular endothelial growth factor (VEGF), was significantly upregulated compared to the other groups. Our findings suggest that overexpressed VEGF and downregulation of inflammatory processes may be critical mechanisms underlying the DBS-induced microvascular changes.
深部脑刺激（DBS）丘脑底核（STN）已成为治疗帕金森病（PD）患者亚组运动症状的公认方法。DBS 为何有效的机制尚不完全清楚，但先前的研究表明，针对 STN 以外的脑结构进行 DBS 可能会改变微血管。然而，这尚未在接受 STN-DBS 的 PD 患者中进行研究。在这里，我们研究了与未接受 STN-DBS 治疗的 PD 患者相比，接受 STN-DBS 的 PD 患者死后 STN 样本中的微血管变化的程度和性质。我们使用免疫组织化学和免疫荧光方法评估了 PD 和 STN-DBS PD 病例的连续 STN 包含脑切片，与年龄匹配的对照进行比较，使用特异性抗体检测毛细血管、黏附连接和紧密连接相关蛋白以及激活的小胶质细胞。通过共聚焦荧光显微镜和立体学方法结合体外成像工具对染色切片中的细胞特征进行定量。我们发现 STN-DBS PD 患者的微血管内皮细胞厚度、长度和密度明显上调，但激活的小胶质细胞密度降低，所有分析的黏附连接和紧密连接相关蛋白显著上调，与非 DBS PD 患者和对照组相比。此外，在 STN-DBS PD 样本中，血管内皮生长因子（VEGF）等血管生成因子的表达明显上调。我们的研究结果表明，过表达的 VEGF 和炎症过程的下调可能是 DBS 诱导的微血管变化的关键机制。
