Chaiqin chengqi decoction ameliorates acute pancreatitis in mice via inhibition of neuron activation-mediated acinar cell SP/NK1R signaling pathways
Chaiqin chengqi decoction ameliorates acute pancreatitis in mice via inhibition of neuron activation-mediated acinar cell SP/NK1R signaling pathways
复制标题
柴芩承气汤通过抑制神经元激活介导的腺泡细胞SP/NK1R信号通路改善小鼠急性胰腺炎
DOI：
10.1016/j.jep.2021.114029
复制
发表时间：
2021-03-31
影响因子：
5.4
通讯作者：
Xia, Qing
中科院分区：
文献类型：
--
作者：
Han, Chenxia;Du, Dan;Xia, Qing
民族药理学相关性：柴芩承气汤（CQCQD）及其衍生物已被广泛应用于急性胰腺炎（AP）的早期治疗。大量的研究表明CQCQD及其衍生物的抗氧化和抗氧化作用，但这些作用是否可以归因于抑制神经源性炎症，从来没有研究过。本研究的目的：研究CQCQD对实验性AP模型中基于P物质（SP）-神经激肽1受体（NK 1 R）的神经源性炎症的作用。对AP患者入院时采用视觉模拟评分法（VAS）进行疼痛评分，同时测定血清SP水平及胰腺SP和NK 1 R的表达。对于体内研究，小鼠每小时接受7次蛙皮素（50 μ g/kg）的腹膜内注射以诱导AP，而对照组接受生理盐水注射。在治疗组中，CQCQD（10 g/kg，200 μ l）在雨蛙肽注射的第三、第五和第七次灌胃给药，或NK 1 R拮抗剂CP 96345（5 mg/kg）在首次雨蛙肽给药前30 min腹腔注射。进行von Frey试验以评价疼痛行为。在第一次雨蛙肽/盐水注射后12小时处死动物以评估严重程度。药理网络分析用于确定CQCQD用于AP和疼痛的活性成分。在体外，用CQCQD（5 mg/ml）、CP 96345（1 μ M）或CQCQD的选定活性化合物预处理新鲜分离的胰腺腺泡细胞（12.5、25和50 μ M）孵育30分钟，然后SP再孵育30分钟。中重度和重度患者VAS评分、血清SP水平和胰腺SP-NK 1 R表达均较轻度患者明显升高。CQCQD，而不是CP 96345，一贯和显着改善疼痛，胰腺坏死，全身炎症在雨蛙素诱导的AP以及抑制胰腺腺泡细胞的NK 1 R内化。CQCQD的这些作用与胰腺SP-NK 1 R和胰腺、背根神经节和脊髓中神经元活性的降低相关。通过药理学网络分析确定的CQCQD的前3个活性成分黄芩苷、大黄素和厚朴酚抑制分离的胰腺腺泡细胞中的NK 1 R内化和NF-κ B信号通路激活。CQCQD通过抑制神经元激活介导的胰腺腺泡细胞SP-NK 1 R信号通路及其活性成分黄芩苷、大黄素、和厚朴酚有助于这种效果。
Ethnopharmacological relevance: Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the antiinflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied.Aim of the study: To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model.Material and methods: For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 mu g/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 mu l) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 mu M), or selected active compounds of CQCQD (12.5, 25, and 50 mu M) for 30 min, followed by SP incubation for another 30 min.Results: The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in ceruleininduced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-kappa B signal pathway activation in isolated pancreatic acinar cells.Conclusions: CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activationmediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.