Anna Thorsø Larsen, Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark. Tel: +45 44525252. Email:
J Prev Alzheimers Dis. 2024;11(4):1122-1131. doi: 10.14283/jpad.2024.74.
Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown.
Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment.
When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213.
In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.
糖尿病，尤其是胰岛素抵抗，与认知功能障碍的发生风险增加相关，这使得抗糖尿病药物成为治疗神经退行性疾病的一种有前景的治疗选择。双重淀粉样肽和降钙素受体激动剂（DACRAs）在血糖控制和胰岛素敏感性方面具有有益作用。然而，DACRAs 是否会影响认知功能尚不清楚。
Zucker 糖尿病肥胖大鼠接受了 DACRA KBP-336（4.5 nmol/kg，每 3 天 1 次）、淀粉样肽类似物 AM1213（25 nmol/kg，每天 1 次）或载体治疗 18 周。此外，通过纳入一组从第 30 天开始治疗的大鼠，评估了 KBP-336 的晚期干预效果。在整个研究过程中评估葡萄糖控制和耐受性，并在治疗 17 周后通过 Morris 水迷宫评估空间学习和记忆。
在评估空间学习时，接受 KBP-336 治疗的大鼠在整个研究过程中的表现明显优于 AM1213、载体和晚期干预 KBP-336。KBP-336 和 AM1213 治疗均改善了空间记忆，优于载体。在认知测试中的整体表现反映在血糖控制的治疗效果上，KBP-336 优于 AM1213。
综上所述，DACRA KBP-336 可改善糖尿病大鼠的糖尿病诱导的空间学习和记忆障碍。此外，KBP-336 改善长期血糖控制的效果优于淀粉样肽类似物 AM1213。综上所述，由于 KBP-336 具有抗糖尿病和胰岛素增敏特性，因此是治疗认知障碍的有前途的候选药物。
