Koumine

Koumine is a major active alkaloid extracted from the traditional Chinese medicinal herb Gelsemium elegans, and it exhibits a variety of pharmacological effects, including anti-inflammatory and immunomodulatory activities^[1-2]. Koumine can modulate the activity of multiple signaling pathways, such as NF-κB, MAPK, and PI3K/Akt^[3]. Studies have shown that Koumine can alleviate neuropathic pain, suppress neuroinflammation, and protect against neuronal damage^[4].

In vitro, treatment of human hepatocellular carcinoma cells (Huh-7 and SNU-449) with Koumine (100–800μg/mL) significantly inhibited cell proliferation and promoted apoptosis. Koumine reduced mitochondrial membrane potential, increased intracellular reactive oxygen species (ROS) levels, and suppressed the phosphorylation of ERK, p38, p65, and IκBα. Additionally, Koumine upregulated the expression of pro-apoptotic proteins cleaved-Caspase-3 and Bax, while downregulating the anti-apoptotic protein Bcl-2^[5]. In RAW264.7 macrophages, pretreatment with Koumine (100–400μg/mL) significantly inhibited lipopolysaccharide (LPS)-induced inflammatory responses. Koumine reduced the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO), and decreased the secretion levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Koumine also inhibited the phosphorylation of p65 and IκBα in the NF-κB signaling pathway and reduced NF-κB DNA-binding activity. Furthermore, Koumine significantly suppressed the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK)^[6].

In vivo, oral administration of Koumine (0.6–15mg/kg/day) to rats with adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) significantly reduced arthritis index scores, mechanical hyperalgesia, and paw swelling. Koumine also inhibited abnormal increases in thymus and liver weights and improved joint space narrowing and bone destruction. Moreover, Koumine significantly decreased the protein and mRNA expression levels of pro-inflammatory cytokines IL-1β and TNF-α in serum and joint tissues, and suppressed the elevation of anti-type II collagen antibodies (anti-CII IgG) in serum ^[7]. In a Sprague-Dawley (SD) rat model of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet, Koumine (0.056, 0.28, and 1.4mg/kg) was administered intraperitoneally once daily for two weeks starting from the 16th week of model establishment. Koumine dose-dependently and significantly reduced serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), while increasing high-density lipoprotein cholesterol (HDL-C) levels. Koumine also decreased the liver index, improved hepatic steatosis, and significantly reduced the production and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17A, IFN-γ) in the liver, while increasing the expression of the anti-inflammatory cytokine IL-10. Additionally, Koumine modulated the proportions of CD4⁺ T cell subsets in the liver, inhibited the differentiation of Th1 and Th17 cells, and promoted the generation of Th2 and Treg cells, thereby exerting immunomodulatory effects and significantly alleviating the pathological progression of NAFLD^[8].

References:
[1] Shoaib RM, Zhang JY, Mao XF, et al. Gelsemine and koumine, principal active ingredients of Gelsemium, exhibit mechanical antiallodynia via spinal glycine receptor activation-induced allopregnanolone biosynthesis. Biochem Pharmacol. 2019 Mar;161:136-148.
[2] Xiong B, Jin G, Xu Y, et al. Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain. Front Pharmacol. 2021 Jun 24;12:692917.
[3] Lin SK, Chen ST, Zhan Y, et al. The alleviatory effects of koumine on MSU-induced gouty arthritis via the TLR4/NF-κB/NLRP3 pathway. Basic Clin Pharmacol Toxicol. 2024 Aug;135(2):133-147.
[4] Xiong B, Zhong Z, Chen C, et al. The anxiolytic effect of koumine on a predatory sound stress-induced anxiety model and its associated molecular mechanisms. Phytomedicine. 2022 Aug;103:154225.
[5] Yuan Z, Liang Z, Yi J, et al. Koumine Promotes ROS Production to Suppress Hepatocellular Carcinoma Cell Proliferation Via NF-κB and ERK/p38 MAPK Signaling. Biomolecules. 2019 Oct 2;9(10):559.
[6] Guo J, Ding W, Cai S, et al. Polydatin radiosensitizes lung cancer while preventing radiation injuries by modulating tumor-infiltrating B cells. J Cancer Res Clin Oncol. 2023 Sep;149(12):9529-9542.
[7] Yang J, Cai HD, Zeng YL, et al. Effects of Koumine on Adjuvant- and Collagen-Induced Arthritis in Rats. J Nat Prod. 2016 Oct 28;79(10):2635-2643.
[8] Yue R, Jin G, Wei S, et al. Immunoregulatory Effect of Koumine on Nonalcoholic Fatty Liver Disease Rats. J Immunol Res. 2019 Feb 17;2019:8325102.

Koumine是从传统中药钩吻（Gelsemium elegans）中提取的一种主要活性生物碱，具有多种药理作用，包括抗炎和免疫调节等^[1-2]。Koumine可调节NF-κB、MAPK和PI3K/Akt等多个信号通路活性^[3]。研究表明，Koumine可缓解神经病理性疼痛、抑制神经炎症，抵抗焦虑，并对神经元损伤具有保护作用^[4]。

在体外，Koumine（100–800μg/mL）处理人肝癌细胞（Huh-7和SNU-449），显著抑制了细胞增殖并促进了细胞凋亡，降低了线粒体膜电位，增加了细胞内活性氧（ROS）水平，抑制了ERK、p38、p65和IκBα的磷酸化，上调了促凋亡蛋白cleaved-Caspase-3和Bax的表达，下调了抗凋亡蛋白Bcl-2的表达^[5]。Koumine（100–400μg/mL）预处理RAW264.7巨噬细胞后，显著抑制了脂多糖（LPS）诱导的炎症反应，降低了诱导型一氧化氮合酶（iNOS）蛋白表达及一氧化氮（NO）的生成，减少了促炎细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的分泌水平。同时，Koumine抑制了核因子κB（NF-κB）信号通路中p65和IκBα的磷酸化，降低了NF-κB的DNA结合活性。此外，Koumine还显著抑制了细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化^[6]。

在体内，Koumine（0.6–15mg/kg/day）通过灌胃方式处理患有佐剂诱导性关节炎（AIA）和胶原诱导性关节炎（CIA）的大鼠，显著减轻了关节炎指数评分、机械性痛觉过敏和足爪肿胀程度，抑制了胸腺和肝脏重量的异常增加，改善了关节间隙狭窄和骨破坏。此外，Koumine还显著降低了血清和关节组织中促炎细胞因子IL-1β和TNF-α的蛋白及mRNA表达水平，并抑制了血清中抗II型胶原抗体（anti-CII IgG）的升高^[7]。Koumine（0.056、0.28和1.4mg/kg）通过腹腔注射给药，用于治疗高脂饮食诱导的非酒精性脂肪性肝病（NAFLD）Sprague-Dawley（SD）大鼠模型，给药时间为模型建立后第16周开始，每日一次，持续两周。Koumine以剂量依赖性方式显著降低NAFLD大鼠血清中的甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、丙氨酸氨基转移酶（ALT）和天门冬氨酸氨基转移酶（AST）水平，升高高密度脂蛋白胆固醇（HDL-C）水平，减少肝脏指数，改善肝细胞脂肪样病变，并显著降低肝脏中促炎细胞因子（TNF-α、IL-1β、IL-6、IL-17A、IFN-γ）的产生和mRNA表达，同时增加抗炎细胞因子IL-10的表达。此外，Koumine还可调节肝脏中CD4+ T细胞亚群的比例，抑制Th1和Th17细胞的分化，促进Th2和Treg细胞的生成，从而发挥免疫调节作用，显著缓解NAFLD的病理进程^[8]。