Department of Neurosurgery, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530001, Guangxi, China.
Department of Neurosurgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511500, Guangdong, China.
Neurotox Res. 2022 Aug;40(4):1020-1028. doi: 10.1007/s12640-022-00495-6. Epub 2022 May 7.
Traumatic brain injury (TBI) is a severe disease of brain damage accompanied by blood-brain barrier (BBB) dysfunction. The BBB is composed of brain microvascular endothelial cells (BMECs), astrocyte terminus, pericytes, and a basement membrane. Tight junction proteins expressed by BMECs play important roles in preserving BBB integrity. Pramipexole is a selective dopamine agonist applied for treating Parkinson's disease and has been recently claimed with neuroprotective capacity. This study will further explore the impact of Pramipexole on tight junctions and BBB integrity to provide the potential treatment strategy for TBI-induced BBB damage. The TBI model was established in mice and was identified by the promoted brain water content, declined Garcia scores, reduced latency of the rotarod test, aggravated pathological changes in the brain cortex, and excessively released inflammatory factors. After treatment with Pramipexole, the neurofunctional deficits, behavioral disability, and aggravated pathological changes were dramatically reversed, accompanied by the alleviated BBB permeability, and upregulated occludin, an important tight junction protein. TBI model cells were established by the scratching bEnd.3 cells method. Cells were stimulated with 10 and 20 μM Pramipexole, followed by exposure to TBI. Increased fluorescence intensity of FITC-dextran, reduced value of TEER, and downregulated occludin and KLF2 were observed in TBI-exposed cells, all of which were greatly reversed by 10 and 20 μM Pramipexole. Furthermore, in KLF2-silenced bEnd.3 cells, the protective ability of Pramipexole against endothelial permeability and the expression level of occludin were dramatically abolished. Collectively, our results suggest that Pramipexole protected against TBI-induced BBB dysfunction by mediating KLF2.
创伤性脑损伤（TBI）是一种严重的脑损伤疾病，伴有血脑屏障（BBB）功能障碍。BBB 由脑微血管内皮细胞（BMECs）、星形胶质细胞终末、周细胞和基底膜组成。BMECs 表达的紧密连接蛋白在维持 BBB 完整性方面发挥着重要作用。普拉克索是一种用于治疗帕金森病的选择性多巴胺激动剂，最近被声称具有神经保护能力。本研究将进一步探讨普拉克索对紧密连接和 BBB 完整性的影响，为 TBI 引起的 BBB 损伤提供潜在的治疗策略。TBI 模型在小鼠中建立，并通过促进脑含水量、降低 Garcia 评分、减少旋转棒试验潜伏期、加重皮质病理变化和过度释放炎症因子来鉴定。用普拉克索治疗后，神经功能缺陷、行为障碍和加重的病理变化得到了显著逆转，同时 BBB 通透性得到了缓解，occludin 等重要的紧密连接蛋白得到了上调。通过划痕 bEnd.3 细胞法建立 TBI 模型细胞。用 10 和 20 μM 普拉克索刺激细胞，然后暴露于 TBI。在 TBI 暴露的细胞中观察到 FITC-葡聚糖的荧光强度增加，TEER 值降低，occludin 和 KLF2 下调，这些都被 10 和 20 μM 普拉克索显著逆转。此外，在 KLF2 沉默的 bEnd.3 细胞中，普拉克索对内皮通透性的保护作用和 occludin 的表达水平被显著消除。总之，我们的结果表明，普拉克索通过调节 KLF2 来保护 TBI 引起的 BBB 功能障碍。
