TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China; Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China.
Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China.
J Ethnopharmacol. 2019 Jun 28;238:111902. doi: 10.1016/j.jep.2019.111902. Epub 2019 Apr 21.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases.
The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models.
The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot.
The maximal tolerated single dose of KHS was determined to be 26 g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200 mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800 mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800 mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100 mg/kg and indomethacin at a dosage of 10 mg/kg were used in both mice and rat models.
These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1β, IL-6, and TNF-α and inhibiting the proteins expression of COX-2 and iNOS.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为炎症自发消退失败。异型南五味子（KHS）的茎是一种著名的抗关节炎土家族民族药用植物，在民间称为雪藤，长期以来一直用于预防和治疗风湿和关节炎疾病。
本研究旨在使用不同的动物模型研究 KHS 的镇痛和抗炎作用及其潜在机制。
采用腹腔注射醋酸引起的小鼠腹部扭曲发作和辐射热刺激引起的尾巴闪烁反应来评估 KHS 的镇痛作用。测量并记录小鼠的腹部扭曲发作次数和大鼠的尾巴闪烁潜伏期。在急性炎症模型中，二甲苯涂于耳表面诱导小鼠耳肿胀，角叉菜胶皮下注射诱导雄性和雌性大鼠右后足肿胀。选择角叉菜胶诱导的大鼠足肿胀作为 KHS 的抗急性炎症机制。通过 ELISA 测量血清中白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子（TNF-α）的水平，并通过 Western blot 检测环加氧酶-1（COX-1）、环加氧酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的蛋白表达。
确定 KHS 在雌雄小鼠中的最大耐受单剂量为 26g/kg。药理研究表明，KHS 剂量为 200mg/kg 时，明显延长了大鼠对辐射热刺激的反应时间，并抑制了腹腔注射醋酸引起的小鼠腹部扭曲发作。KHS 剂量为 200、400 和 800mg/kg 时，对二甲苯诱导的小鼠耳肿胀具有剂量依赖性抑制作用。KHS 剂量为 100、200、400 和 800mg/kg 时，对角叉菜胶诱导的大鼠皮下注射引起的足肿胀具有剂量和时间依赖性抑制作用。机制研究表明，KHS 的抗炎作用与抑制促炎细胞因子 IL-1β、IL-6 和 TNF-α的产生有关，并有效降低了角叉菜胶注射大鼠血清、足组织和炎症渗出物中 COX 和 iNOS 蛋白的表达。阳性参比药物，罗通定剂量为 100mg/kg，吲哚美辛剂量为 10mg/kg，分别用于小鼠和大鼠模型。
这些结果表明，KHS 对镇痛和抗炎有显著作用，可降低促炎细胞因子 IL-1β、IL-6 和 TNF-α的水平，并抑制 COX-2 和 iNOS 蛋白的表达。
