RAGE抑制剂FPS-ZM1对db/db小鼠抑郁的影响及机制

Effect and mechanism of RAGE inhibitor FPS-ZM1 on depression in db/db mice

目的阐明晚期糖基化终末产物受体(RAGE)抑制剂FPS-ZM1影响2型糖尿病模型(db/db)小鼠抑郁的分子机制。方法雄性6~8周龄db/db小鼠24只,随机分为2型糖尿病组(db/db)、糖尿病给药组[db/db+FPS,FPS-ZM1腹腔注射1.0 mg/(kg·d)]、糖尿病溶剂对照组(db/db+Oil,小鼠给予同等体积的玉米油腹腔注射)。另外8只同周龄的雄性db/m小鼠作为正常对照。给药12周后,悬尾实验和强迫游泳实验检测小鼠的抑郁样行为,TUNEL染色法检测小鼠海马区神经元的凋亡情况,免疫印迹技术检测小鼠海马区RAGE、NOD样受体蛋白3(NLRP3)、白介素-1β(IL-1β)以及半胱氨酸蛋白酶-1(Caspase-1)的表达情况。结果db/db小鼠出现抑郁症状,FPS-ZM1能够改善其抑郁样症状;db/db小鼠海马区神经元的凋亡率显著高于db/m小鼠(P<0.01),FPS-ZM1能够显著降低db/db小鼠海马神经元的凋亡率(P<0.01);db/db小鼠海马区RAGE、NLRP3、IL-1β以及Caspase-1的表达显著高于db/m小鼠(P<0.01),FPS-ZM1能够抑制RAGE、NLRP3、IL-1β以及Caspase-1的表达。结论FPS-ZM1通过抑制RAGE及其下游NLRP3信号通路,降低海马神经元凋亡,改善糖尿病小鼠的抑郁症状。

Objective To elucidate the molecular mechanism of receptor for advanced glycation end products(RAGE)inhibitor FPS-ZM1 in the treatment of depression in db/db mice.Methods 24 male db/db mice aged 6-8 weeks were randomly divided into type 2 diabetic group(db/db group),diabetic treatment group[db/db+FPS,FPS-ZM11.0 mg/(kg·d)was administered intraperitoneally]and diabetic solvent control group(db/db+Oil,mice were injected intraperitoneally corn oil with the same volume).The other 8 male db/m mice aged the same weeks were used as normal control.After administrating drugs for 12 weeks,the depression-like behavior of mice was detected by tail suspension and forced swimming test,the apoptosis of neurons in mice hippocampus was detected by TUNEL staining,and the expression of RAGE,nod-like receptor protein 3(NLRP3),interleukin-1β(IL-1β)and cysteinyl aspartate specific proteinase-1(Caspase-1)in mice hippocampus was detected by Western blot.Results In behavioral experiments db/db mice showed depressive symptoms,which could be improved by FPS-ZM1.Compared with db/m mice,the apoptosis rate of hippocampal neurons in db/db mice was significantly higher(P<0.01),which could also be significantly reduced by FPS-ZM1(P<0.01).The expressions of RAGE,NLRP3,IL-1βand Caspase-1 in the hippocampus of db/db mice were significantly higher than those of db/m mice(P<0.01)and FPS-ZM1 could still inhibit the expression of these proteins.Conclusion FPS-ZM1 can reduce the apoptosis of hippocampal neurons by inhibiting RAGE and its downstream NLRP3 signal pathway,and eventually improve the depressive symptoms of diabetic mice.