Li Xun, Huang Xi, Tang Yuanlin, Zhao Fangli, Cao Yanmei, Yin Lian, Li Guochun
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Wujin Vocational School, Changzhou, China.
Front Pharmacol. 2018 Nov 6;9:1169. doi: 10.3389/fphar.2018.01169. eCollection 2018.
Intracerebral hemorrhage is a fatal subtype of stroke, with crucial impact on public health. Surgical removal of the hematoma as an early-stage treatment for ICH can't improve long-term prognosis remarkably. Liangxue tongyu prescription (LP), a Traditional Chinese Medicine (TCM) formula, includes eight ingredients and has been used to treat ICH in the clinical. In the study, we elucidated the pharmacological efficacy and therapeutic efficacy of LP to dissect the mechanism of LP against ICH via network analysis and experimental validation. First, we discovered 34 potential compounds and 146 corresponding targets in LP based on network prediction. 24 signal pathway were obtained by the Clue Go assay based on potential compounds in LP against ICH. Second, we found that LP can not only decreased the level of high sensitive C reactive protein (HS-CRP), tumor necrosis factor-α (TNF-α), NF-kβ, D-dimmer (D2D), estradiol (E2), S-100B, neuron specific enolase (NSE), and interleukin 1 (IL-1) in plasma on spontaneously hypertensive rats (SHRs), but also promoted cell proliferation and inhibited cell apoptosis on the glutamate-induced PC12 cell. The compounds including Taurine, Paeonol, and Ginsenoside Rb1 in LP can activate PI3K/AKT pathway. Third, from the three-factor two-level factorial design, compound combinations in LP, such as Taurine and Paeonol, Taurine and Geniposide, Ginsenoside Rg1, and Ginsenoside Rb1, had first-level interactions on cell proliferation. Compound combinations including Taurine and Paeonol, Ginsenoside Rg1 and Ginsenoside Rb1 had as significant increase in efficiency on inhibiting the apoptosis of PC12 cells at the low concentration and up-regulating of PI3K and AKT. Overall, our results suggested that LP had integrated therapeutic effect on ICH due to activities of anti-inflammatory, anti-coagulation, blood vessel protection, and protection neuron from excitotoxicity based on the way of "multi-component, multi-target, multi-pathway," and compound combination in LP can offer protection neuron from excitotoxicity at the low concentration by activation of the PI3K/Akt signal pathway.
脑出血是中风的一种致命亚型，对公众健康有至关重要的影响。手术清除血肿作为脑出血的早期治疗方法并不能显著改善长期预后。凉血通瘀方（LP）是一种中药配方，由八味药组成，已在临床上用于治疗脑出血。在本研究中，我们通过网络分析和实验验证阐明了凉血通瘀方的药理作用和治疗效果，以剖析其治疗脑出血的机制。首先，基于网络预测，我们在凉血通瘀方中发现了34种潜在化合物和146个相应靶点。通过基于凉血通瘀方抗脑出血潜在化合物的Clue Go分析获得了24条信号通路。其次，我们发现凉血通瘀方不仅能降低自发性高血压大鼠（SHRs）血浆中高敏C反应蛋白（HS-CRP）、肿瘤坏死因子-α（TNF-α）、NF-kβ、D-二聚体（D2D）、雌二醇（E2）、S-100B、神经元特异性烯醇化酶（NSE）和白细胞介素1（IL-1）的水平，还能促进谷氨酸诱导的PC12细胞增殖并抑制其凋亡。凉血通瘀方中的牛磺酸、丹皮酚和人参皂苷Rb1等化合物可激活PI3K/AKT通路。第三，从三因素两水平析因设计来看，凉血通瘀方中的化合物组合，如牛磺酸和丹皮酚、牛磺酸和栀子苷、人参皂苷Rg1与人参皂苷Rb1，对细胞增殖有一级相互作用。包括牛磺酸和丹皮酚、人参皂苷Rg1与人参皂苷Rb1的化合物组合在低浓度时对抑制PC12细胞凋亡和上调PI3K及AKT有显著增效作用。总体而言，我们的结果表明，凉血通瘀方基于“多成分、多靶点、多途径”的方式，具有抗炎、抗凝、血管保护和保护神经元免受兴奋毒性的活性，对脑出血具有综合治疗作用，且凉血通瘀方中的化合物组合可通过激活PI3K/Akt信号通路在低浓度时保护神经元免受兴奋毒性。
