血府逐瘀汤通过调节腺苷改善急性创伤性脑损伤大鼠的血脑屏障完整性

Xuefu Zhuyu Decoction Improves Blood-Brain Barrier Integrity in Acute Traumatic Brain Injury Rats via Regulating Adenosine.

作者信息

Wang Yang, Yan Qiu-Ju, Hu En, Wu Yao, Ding Ruo-Qi, Chen Quan, Cheng Meng-Han, Yang Xi-Ya, Tang Tao, Li Teng

机构信息

Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.

NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha, 410008, China.

出版信息

Chin J Integr Med. 2025 Jan 8. doi: 10.1007/s11655-025-4200-7.

DOI:10.1007/s11655-025-4200-7

PMID:39776039

Abstract

OBJECTIVE

To explore the neuroprotective effects of Xuefu Zhuyu Decoction (XFZYD) based on in vivo and metabolomics experiments.

METHODS

Traumatic brain injury (TBI) was induced via a controlled cortical impact (CCI) method. Thirty rats were randomly divided into 3 groups (10 for each): sham, CCI and XFZYD groups (9 g/kg). The administration was performed by intragastric administration for 3 days. Neurological functions tests, histology staining, coagulation and haemorheology assays, and Western blot were examined. Untargeted metabolomics was employed to identify metabolites. The key metabolite was validated by enzyme-linked immunosorbent assay and immunofluorescence.

RESULTS

XFZYD significantly alleviated neurological dysfunction in CCI model rats (P<0.01) but had no impact on coagulation function. As evidenced by Evans blue and IgG staining, XFZYD effectively prevented blood-brain barrier (BBB) disruption (P<0.05, P<0.01). Moreover, XFZYD not only increased the expression of collagen IV, occludin and zona occludens 1 but also decreased matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2), which protected BBB integrity (all P<0.05). Nine potential metabolites were identified, and all of them were reversed by XFZYD. Adenosine was the most significantly altered metabolite related to BBB repair. XFZYD significantly reduced the level of equilibrative nucleoside transporter 2 (ENT2) and increased adenosine (P<0.01), which may improve BBB integrity.

CONCLUSIONS

XFZYD ameliorates BBB disruption after TBI by decreasing the levels of MMP-9 and COX-2. Through further exploration via metabolomics, we found that XFZYD may exert a protective effect on BBB by regulating adenosine metabolism via ENT2.

摘要

目的

基于体内实验和代谢组学实验探讨血府逐瘀汤（XFZYD）的神经保护作用。

方法

采用控制性皮质撞击（CCI）法诱导创伤性脑损伤（TBI）。将30只大鼠随机分为3组（每组10只）：假手术组、CCI组和XFZYD组（9 g/kg）。通过灌胃给药3天。检测神经功能、组织学染色、凝血和血液流变学指标以及蛋白质免疫印迹法。采用非靶向代谢组学鉴定代谢物。通过酶联免疫吸附测定和免疫荧光对关键代谢物进行验证。

结果

XFZYD显著减轻CCI模型大鼠的神经功能障碍（P<0.01），但对凝血功能无影响。伊文思蓝和IgG染色表明，XFZYD有效预防血脑屏障（BBB）破坏（P<0.05，P<0.01）。此外，XFZYD不仅增加了IV型胶原、闭合蛋白和紧密连接蛋白1的表达，还降低了基质金属蛋白酶-9（MMP-9）和环氧化酶-2（COX-2），从而保护了BBB的完整性（均P<0.05）。鉴定出9种潜在代谢物，且均被XFZYD逆转。腺苷是与BBB修复相关变化最显著的代谢物。XFZYD显著降低平衡核苷转运体2（ENT2）水平并增加腺苷（P<0.01），这可能改善BBB的完整性。