School of Traditional Chinese Medicine Department, Beijing University of Chinese Medicine, 11 Beisanhuandong Road, Chaoyang District, Beijing 100029, China.
Oxid Med Cell Longev. 2020 Oct 10;2020:1201624. doi: 10.1155/2020/1201624. eCollection 2020.
Ischemic stroke (IS) can disrupt various types of brain cells in the neurovascular unit (NVU) at both the structural and functional levels. Therefore, NVU is considered to be a more comprehensive target for the treatment of IS. It is necessary to develop drugs which targeted multiple mechanisms and cell types on NVU against IS. As a component of bile acid, cholic acid has been reported to be able to diffuse across phospholipid bilayers and further cross the blood-brain barrier (BBB). However, the effects exerted by cholic acid (CA) on the NVU after stroke remain unclear. Based on our previous research, we established and further supplemented the characteristics of the functional in vitro NVU model and its oxygen-glucose deprivation and reoxygenation (OGD/R) model. Then, we investigated the effect of CA on the maintenance of the in vitro NVU after OGD/R and further discussed the specific molecular targets that CA played a role in. For the first time, we found that CA significantly maintained BBB integrity, downregulated apoptosis, and mitigated oxidative stress and inflammation damage after OGD/R. Meanwhile, CA obviously increased the levels of brain-derived neurotrophic factor (BDNF), which were mainly secreted from astrocytes, in the coculture system after OGD/R. The results demonstrated that CA significantly increased the expression of TrkB, PI3K/Akt, MAPK/Erk, and CREB in neurons. These positive effects on the downstream proteins of BDNF were suppressed by treatment with ANA12 which is an inhibitor of TrkB. In conclusion, the present study demonstrates that CA exerted multiple protective effects on the NVU, mediated by increasing the release of BDNF and further stimulating the BDNF-TrkB-PI3K/Akt and BDNF-TrkB-MAPK/Erk signaling pathways in the context of OGD/R-induced injury. These findings indicate that CA possesses the effect of antagonizing multiple mechanisms of IS and protecting multiple cell types in NVU and may be useful as a treatment for IS.
缺血性脑卒中（IS）可在结构和功能水平上破坏神经血管单元（NVU）中的各种类型的脑细胞。因此，NVU 被认为是治疗 IS 的更全面的靶点。有必要开发针对 IS 作用于 NVU 的多种机制和细胞类型的药物。作为胆酸的一种成分，胆酸已被报道能够扩散穿过磷脂双层，进一步穿过血脑屏障（BBB）。然而，胆酸（CA）在脑卒中后对 NVU 的影响尚不清楚。基于我们之前的研究，我们建立并进一步补充了体外 NVU 模型及其氧葡萄糖剥夺和再氧合（OGD/R）模型的功能特征。然后，我们研究了 CA 对 OGD/R 后体外 NVU 维持的影响，并进一步讨论了 CA 发挥作用的特定分子靶点。我们首次发现，CA 能显著维持 BBB 的完整性，下调细胞凋亡，并减轻 OGD/R 后的氧化应激和炎症损伤。同时，CA 明显增加了 OGD/R 后共培养体系中脑源性神经营养因子（BDNF）的水平，BDNF 主要由星形胶质细胞分泌。结果表明，CA 明显增加了神经元中 TrkB、PI3K/Akt、MAPK/Erk 和 CREB 的表达。BDNF 的下游蛋白的这些正向作用被 TrkB 的抑制剂 ANA12 抑制。总之，本研究表明 CA 通过增加 BDNF 的释放，对 OGD/R 诱导损伤后的 BDNF-TrkB-PI3K/Akt 和 BDNF-TrkB-MAPK/Erk 信号通路发挥多种保护作用，对 NVU 具有拮抗 IS 多种机制和保护 NVU 多种细胞类型的作用，可能有助于治疗 IS。
