摘要
目的:探讨苦参碱通过激活小鼠苦味受体成员4(mTAS2R4)改善糖尿病性认知功能障碍(DACD)的作用及机制。方法:取雄性C57BL/6小鼠,连续5 d腹腔注射50 mg/kg链脲佐菌素(STZ)诱导建立DACD模型。将造模成功小鼠分为模型组、苦参碱低剂量(20 mg/kg)组、苦参碱高剂量(40 mg/kg)组和mTAS2R4激动剂奎宁(80 mg/kg)组,每组9只。另选同周龄9只小鼠作为正常组。采用Morris水迷宫和新物体识别测试评估DACD小鼠的学习、记忆功能,苏木精—伊红(HE)染色法观察海马神经元病理变化,免疫蛋白印迹(western blotting)法检测I-κB激酶β(IKKβ)/核因子κB亚基(NF-κB)信号通路蛋白、NLR家族pyrin域蛋白3(NLRP3)、Caspase-1、白细胞介素-1β(IL-1β)、mTAS2R4和磷脂酶Cβ2(PLCβ2)蛋白表达。结果:苦参碱低、高剂量组和奎宁组小鼠空腹血糖(FBG)、体质量和学习、记忆功能均改善(均P<0.01)。与正常组相比,模型组小鼠海马CA1区和CA3区神经元数目减少,p-IKKβ/IKKβ比值、p-NF-κB p65/NF-κB p65比值及NLRP3、Caspase-1和IL-1β蛋白表达水平升高,mTAS2R4和PLCβ2蛋白表达水平降低(均P<0.01)。与模型组比较,苦参碱低、高剂量组和奎宁组海马神经元数目增加,p-IKKβ/IKKβ比值、p-NF-κB p65/NF-κB p65比值及NLRP3、Caspase-1和IL-1β蛋白表达水平降低(均P<0.05)。苦参碱高剂量组mTAS2R4和PLCβ2蛋白表达水平均升高(均P<0.01)。苦参碱低剂量组PLCβ2蛋白表达水平升高(P<0.05)。结论:苦参碱够能激活脑内mTAS2R4受体信号,抑制神经炎症反应,从而改善DACD小鼠的认知功能障碍。
Objective:To investigate the effect and mechanism of matrine in improving diabetes-associated cognitive dysfunction(DACD)from activation of mouse bitter taste receptor member 4(mTAS2R4).Methods:Male C57BL/6 mice were induced to establish the DACD model by intraperitoneal injection of streptozotocin(STZ)(50 mg/kg)for 5 consecutive days.The successfully modeled mice were divided into model group,low-dose matrine group(20 mg/kg),high-dose matrine group(40 mg/kg),and mTAS2R4 agonist quinine group(80 mg/kg),with 9 mice in each group.Additionally,another 9 mice of the same age were selected as normal control group.The Morris water maze and novel object recognition tests were used to evaluate the learning and memory functions in DACD mice.Hematoxylin-eosin(HE)staining was used to examine the pathological changes of the hippocampal neurons.Western blotting was performed to detect the protein expression of IKKβ/NF-κB signaling pathway-related proteins,NLRP3,Caspase-1,interleukin-1β(IL-1β),mTAS2R4,and phospholipase Cβ2(PLCβ2).Results:In the low-dose matrine,high-dose matrine and quinine groups,fasting blood glucose(FBG),body weight,and the learning and memory functions of mice were all improved(all P<0.01).Compared with the normal group,the number of hippocampal neurons in CA1 and CA3 regions of mice in the model group was decreased,and the ratios of p-IKKβ/IKKβand p-NF-κB p65/NF-κB p65,as well as the protein expression levels of NLRP3,Caspase-1,and IL-1β,were all increased,while the protein expression levels of mTAS2R4 and PLCβ2 were decreased(all P<0.01).Compared with the model group,the number of hippocampal neurons in the lowdose matrine,high-dose matrine,and quinine groups was increased and the ratios of p-IKKβ/IKKβand p-NF-κB p65/NF-κB p65,as well as the protein expression levels of NLRP3,Caspase-1,and IL-1β,were decreased(all P<0.05).In the high-dose matrine group,the protein expression levels of mTAS2R4 and PLCβ2 were both increased(all P<0.01).In the low-dose matrine group,the protein expression of PLCβ2 was upregulated(P<0.05).Conclusion:Matrine can activate the mTAS2R4 receptor signaling in the brain and inhibit neuroinflammatory responses,thereby improving cognitive dysfunction in DACD mice.
作者
王德铭
刘淑清
凌心
刘耀武
WANG Deming;LIU Shuqing;LING Xin;LIU Yaowu(School of Pharmacy,Xuzhou Medical University,Xuzhou 221004,China;Department of Pharmacy,Xuzhou Cancer Hospital,Xuzhou 221005,China)
出处
《广西医科大学学报》
2025年第4期526-532,共7页
Journal of Guangxi Medical University
基金
2024年徐州市卫生健康委医学科技创新项目(No.XWKYHT20240120)。
关键词
苦味受体成员4
苦参碱
糖尿病性认知功能障碍
神经炎症
bitter taste receptor member 4
matrine
diabetes-associated cognitive dysfunction
neuroinflammation
