PDF(Pubmed)
Abstract：
BACKGROUND: Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats.
METHODS: We evaluated KBP-336\'s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology.
RESULTS: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues.
CONCLUSIONS: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.
METHODS: We evaluated KBP-336\'s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology.
RESULTS: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues.
CONCLUSIONS: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.
摘要：
背景：尽管进行了广泛的研究以提供改善疾病的骨关节炎药物（DMOAD），仍然没有批准的DMOAD。胰淀素和降钙素受体双激动剂（DACRA）可以提供代谢益处以及抗伤害感受和潜在的结构保留作用。在这些研究中,我们在半月板切除（MNX）大鼠的OA代谢模型上测试了名为KBP-336的DACRA。
方法：我们使用vonFrey测试评估了KBP-336对接受半月板切除术的高脂饮食（HFD）的SpragueDawley（SD）大鼠疼痛样症状的影响。测量50％的爪退缩阈值（PWT），并使用单向ANOVA进行分析。短体内研究和体外细胞受体表达系统用于说明受体药理学。
结果：进行HFD30周后，包括8周的治疗,接受KBP-3364.5nmol/Kg/72小时的雌性MNX动物的体重较低，脂肪组织较小。在HFD上20周后，包括8周的治疗,接受KBP-336的雄性大鼠的体重低于载体组。在雌性和雄性老鼠中，接受KBP-336治疗的MNX组的PWT高于接受载体治疗的MNX组.为了确定影响疼痛缓解的受体，将KBP-336与长效人降钙素(hCTA)进行比较。对12周龄雄性大鼠的单剂量研究表明，hCTA降低CTX-I而不影响食物摄入，证实其降钙素受体选择性。在18周HFD代谢OA模型上，包括6周的治疗，与媒介物处理的MNX动物相比,100nmol/Kg/24小时的hCTA和0.5、1.5和4.5nmol/Kg/72小时的KBP-336在MNX动物中产生显著更高的PWT。0.5nmol/Kg的hCTA和KBP-336不影响体重和脂肪组织。
结论：总体而言，KBP-336改善了在代谢OA模型中观察到的疼痛。降钙素受体激活被证明是这种抗伤害作用必不可少的。
方法：我们使用vonFrey测试评估了KBP-336对接受半月板切除术的高脂饮食（HFD）的SpragueDawley（SD）大鼠疼痛样症状的影响。测量50％的爪退缩阈值（PWT），并使用单向ANOVA进行分析。短体内研究和体外细胞受体表达系统用于说明受体药理学。
结果：进行HFD30周后，包括8周的治疗,接受KBP-3364.5nmol/Kg/72小时的雌性MNX动物的体重较低，脂肪组织较小。在HFD上20周后，包括8周的治疗,接受KBP-336的雄性大鼠的体重低于载体组。在雌性和雄性老鼠中，接受KBP-336治疗的MNX组的PWT高于接受载体治疗的MNX组.为了确定影响疼痛缓解的受体，将KBP-336与长效人降钙素(hCTA)进行比较。对12周龄雄性大鼠的单剂量研究表明，hCTA降低CTX-I而不影响食物摄入，证实其降钙素受体选择性。在18周HFD代谢OA模型上，包括6周的治疗，与媒介物处理的MNX动物相比,100nmol/Kg/24小时的hCTA和0.5、1.5和4.5nmol/Kg/72小时的KBP-336在MNX动物中产生显著更高的PWT。0.5nmol/Kg的hCTA和KBP-336不影响体重和脂肪组织。
结论：总体而言，KBP-336改善了在代谢OA模型中观察到的疼痛。降钙素受体激活被证明是这种抗伤害作用必不可少的。
