Department of Neurology, Ya'an Peoples Hospital, Ya'an, 625000, Sichuan, China.
Department of Neurology, The Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People's Hospital, Chengdu, 610000, Sichuan, China.
Neurotox Res. 2021 Dec;39(6):2018-2028. doi: 10.1007/s12640-021-00429-8. Epub 2021 Oct 28.
Hyperhomocysteinemia (HHcy)-related brain vascular disorders and brain endothelial dysfunction are important characteristics of the pathogeneses of subarachnoid hemorrhage and stroke. Upregulated homocysteine (Hcy) can impair the integrity of the blood-brain barrier (BBB). Opicapone has been recently licensed for the management of Parkinson's disease (PD); however, it is unknown whether it possesses a protective effect in brain vessels against HHcy. To investigate the beneficial effects of Opicapone on BBB permeability against HHcy, we carried out both in vivo and in vitro experiments. Mice were allocated into four groups: the Control, Opicapone, HHcy, and HHcy + Opicapone. Interestingly, we found that the administration of Opicapone attenuated the increased BBB permeability in Hcy-treated mice, as determined by sodium fluorescein staining. The immunofluorescence staining showed that Opicapone prevented homocysteine-induced reduction of claudin-2 in the mice cortices. The in situ zymography assay revealed that Opicapone suppressed homocysteine-increased matrix metalloproteinases (MMPs) activity in the cortices. In bEnd.3 brain endothelial cells, Opicapone treatment ameliorated homocysteine-induced lactate dehydrogenase (LDH) release and expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Furthermore, Opicapone alleviated homocysteine-induced decrease in claudin-2 level in bEnd.3 cells. In summary, our results show that Opicapone protects against HHcy-induced BBB permeability by reducing the expression and gelatinase activity of MMPs, and increasing the expression of claudin-2.
高同型半胱氨酸血症（HHcy）相关的脑血管疾病和脑内皮功能障碍是蛛网膜下腔出血和中风发病机制的重要特征。同型半胱氨酸（Hcy）上调可损害血脑屏障（BBB）的完整性。奥匹卡朋最近被批准用于治疗帕金森病（PD）；然而，它是否对 HHcy 引起的脑血管具有保护作用尚不清楚。为了研究奥匹卡朋对 HHcy 引起的 BBB 通透性的有益影响，我们进行了体内和体外实验。将小鼠分为四组：对照组、奥匹卡朋组、HHcy 组和 HHcy+奥匹卡朋组。有趣的是，我们发现奥匹卡朋给药可减轻 Hcy 处理小鼠 BBB 通透性的增加，这通过荧光素钠染色确定。免疫荧光染色显示，奥匹卡朋可防止同型半胱氨酸诱导的小鼠皮质中 Claudin-2 减少。原位酶谱测定显示，奥匹卡朋抑制同型半胱氨酸增加的皮质中基质金属蛋白酶（MMPs）活性。在 bEnd.3 脑内皮细胞中，奥匹卡朋处理可改善同型半胱氨酸诱导的乳酸脱氢酶（LDH）释放和基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的表达。此外，奥匹卡朋可减轻同型半胱氨酸诱导的 bEnd.3 细胞 Claudin-2 水平降低。总之，我们的结果表明，奥匹卡朋通过降低 MMPs 的表达和明胶酶活性以及增加 Claudin-2 的表达来保护 BBB 免受 HHcy 诱导的通透性增加。
