黄芩基于PI3K/AKT/GSK3β/β-catenin通路对慢性皮质酮诱导的抑郁小鼠神经发生的影响

Effects of Radix Scutellariae on neurogenesis in chronic corticosterone-induced depression mouse based on PI3K/AKT/GSK3β/β-catenin signaling pathway

目的:研究黄芩对慢性皮质酮诱导的抑郁小鼠神经发生的影响并探讨可能机制。方法:将50只雌性C57BL/6J小鼠随机分为空白组、模型组、艾斯西酞普兰组、黄芩低剂量组及黄芩高剂量组,慢性皮质酮皮下注射6周诱导抑郁模型小鼠,造模3周后再给予艾斯西酞普兰10 mg/kg,黄芩0.75、1.5 g/kg治疗3周。给药结束后进行糖水偏好、悬尾、强迫游泳、开场、新颖摄食行为学测试,ELISA检测血清皮质酮含量,免疫组化检测海马齿状回Ki-67及BrdU阳性细胞数,Western Blot检测PI3K/AKT/GSK3β/β-catenin通路蛋白表达。结果:与空白组比较,模型组糖水偏好率显著降低(P<0.01),悬尾和强迫游泳实验中不动时间显著延长(P<0.01),新颖摄食实验中摄食潜伏期显著增加(P<0.01)、食物消耗率显著降低(P<0.01),血清皮质酮含量显著升高(P<0.01),海马齿状回Ki-67及BrdU阳性细胞数显著降低(P<0.01),海马组织p-PI3K、p-AKT、p-GSK3β、β-catenin蛋白表达显著下调(P<0.01);与模型组比较,艾斯西酞普兰组和黄芩高剂量组糖水偏好、悬尾、强迫游泳、新颖摄食行为学指标显著改善(P<0.01,P<0.05),黄芩低剂量组悬尾、强迫游泳、新颖摄食潜伏期指标显著改善(P<0.01,P<0.05),艾斯西酞普兰组及黄芩高剂量组p-PI3K、p-AKT、p-GSK3β、β-catenin蛋白表达显著上调(P<0.01,P<0.05),黄芩低剂量组p-AKT、β-catenin蛋白表达上调(P<0.01,P<0.05)。结论:黄芩可改善慢性皮质酮抑郁模型小鼠的抑郁样行为,促进神经发生,其作用机制可能与PI3K/AKT/GSK3β/β-catenin信号通路相关。

Objective: To study the effects of Radix Scutellariae on neurogenesis in chronic corticosterone-induced depression mouse and explore its possible mechanism. Methods: Fifty female C57BL/6J mice were randomly divided into control group,model group,escitalopram group,Radix Scutellariae low-dose group and high-dose group. Chronic corticosterone was injected subcutaneously for 6 weeks to induce depression model mice. After 3 weeks,the other three groups except the control group were treated with escitalopram 10 mg/kg,Radix Scutellariae 0.75 and 1.5 g/kg for 3 weeks. The sucrose preference test,tail suspension test,forced swimming test,open field test,novelty-suppressed feeding tests were used to evaluate the depressivelike behaviors after the administration. ELISA was used to detect serum corticosterone content. Immunohistochemistry was used to detect the number of Ki-67 and BrdU positive cells in the hippocampal dentate gyrus. Western Blot was used to detect PI3K/AKT/GSK3β/β-catenin pathway proteins expression. Results: Compared with the control group,the mice’s sucrose preference rate decreased(P<0.01),the immobility time in the tail suspension and forced swimming experiment was prolonged(P<0.01),the incubation period increased(P<0.01),the feeding rate decreased in the novel feeding experiment(P<0.01),and the serum corticosterone content increased(P<0.01) after 6 weeks corticosterone injecting. The number of Ki-67 and BrdU positive cells in the hippocampal dentate gyrus were also significantly reduced(P<0.01),and the protein expressions of p-PI3K,p-AKT,p-GSK3β and β-catenin in hippocampus tissue were significantly down-regulated(P<0.01). Compared with model group,the behaviors indicators of sucrose preference test,tail suspension test,forced swimming test,novelty-suppressed feeding tests in escitalopram group and Radix Scutellariae high-dose group were significantly improved(P<0.01,P<0.05),the tail suspension test,forced swimming test and incubation period in the Radix Scutellariae low-dose group were significantly improved(P<0.01,P<0.05). The protein expressions of p-PI3K,p-AKT,p-GSK3β and β-catenin were significantly up-regulated in escitalopram group and Radix Scutellariae high-dose group(P<0.01,P<0.05),and p-AKT and β-catenin were up-regulated in Radix Scutellariae low-dose group(P<0.01,P<0.05). Conclusion: Radix Scutellariae can alleviate chronic corticosterone-induced depressive-like behaviors and promote neurogenesis of adult-born hippocampal granule cells. Its mechanism may be closely related to the PI3K/AKT/GSK3β/β-catenin signaling pathway.