Centre for Drug Research, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.
Analytical Biochemistry Research Centre, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.
Brain Res Bull. 2019 Oct;152:63-73. doi: 10.1016/j.brainresbull.2019.07.010. Epub 2019 Jul 10.
Cerebral hypoperfusion involved a reduction in cerebral blood flow, leading to neuronal dysfunction, microglial activation and white matter degeneration. The effects on the blood-brain barrier (BBB) however, have not been well-documented. Here, two-vessel occlusion model was adopted to mimic the condition of cerebral hypoperfusion in Sprague-Dawley rats. The BBB permeability to high and low molecular weight exogenous tracers i.e. Evans blue dye and sodium fluorescein respectively, showed marked extravasation of the Evans blue dye in the frontal cortex, posterior cortex and thalamus-midbrain at day 1 following induction of cerebral hypoperfusion. Transmission electron microscopy revealed brain endothelial cell and astrocyte damages including increased pinocytotic vesicles and formation of membrane invaginations in the endothelial cells, and swelling of the astrocytes' end-feet. Investigation on brain microvessel protein expressions using two-dimensional (2D) gel electrophoresis coupled with LC-MS/MS showed that proteins involved in mitochondrial energy metabolism, transcription regulation, cytoskeleton maintenance and signaling pathways were differently expressed. The expression of aconitate hydratase, heterogeneous nuclear ribonucleoprotein, enoyl Co-A hydratase and beta-synuclein were downregulated, while the opposite observed for calreticulin and enhancer of rudimentary homolog. These findings provide insights into the BBB molecular responses to cerebral hypoperfusion, which may assist development of future therapeutic strategies.
脑灌注不足涉及脑血流量减少，导致神经元功能障碍、小胶质细胞激活和白质退化。然而，其对血脑屏障（BBB）的影响尚未得到很好的记录。在这里，采用了两血管闭塞模型来模拟脑灌注不足的情况在 Sprague-Dawley 大鼠中。BBB 对高分子和低分子外源示踪剂（即 Evans 蓝染料和荧光素钠）的通透性显示，在脑灌注不足诱导后第 1 天，前额皮质、后皮质和丘脑-中脑的 Evans 蓝染料明显外渗。透射电子显微镜显示脑内皮细胞和星形胶质细胞损伤，包括内皮细胞中内吞小泡增加和膜内陷形成，以及星形胶质细胞终足肿胀。使用二维（2D）凝胶电泳结合 LC-MS/MS 对脑微血管蛋白表达的研究表明，参与线粒体能量代谢、转录调节、细胞骨架维持和信号通路的蛋白质表达不同。异柠檬酸水解酶、异质核核糖核蛋白、烯酰辅酶 A 水合酶和β-突触核蛋白的表达下调，而钙网蛋白和原始同源增强子的表达则相反。这些发现为 BBB 对脑灌注不足的分子反应提供了深入了解，这可能有助于未来治疗策略的发展。
