加味百合地黄汤对围绝经期抑郁症模型大鼠HPO轴和雌激素受体表达的影响

Effects of Jiawei Baihe Dihuang Decoction on HPO axis and estrogen receptor expression in perimenopausal depression model rats

目的基于下丘脑-垂体-卵巢(hypothalamic-pituitary-ovarian,HPO)轴及雌激素受体(estrogen receptor,ER)探明加味百合地黄汤治疗围绝经期抑郁症的功效及潜在机制。方法将大鼠随机分为正常对照组、模型组、阳性药物组(氟哌噻吨美利曲水溶液1.89 mg/kg)以及加味百合汤高、中、低剂量组(16.2 g/kg、8.1 g/kg、4.05 g/kg),每组10只。除正常对照组外,其他组均采用双侧卵巢摘除联合慢性不可预见性应激建立围绝经期抑郁症大鼠模型。各组给药21 d后采用糖水偏好实验和强迫游泳实验评价大鼠抑郁样行为,酶联免疫吸附法检测血清促性腺激素释放激素(gonadotropin-releasing hormone,GnRH)、卵泡刺激素(follicle-stimulating hormone,FSH)、黄体生成素(luteinizing hormone,LH)、雌二醇(estradiol,E2)含量,HE染色观察下丘脑、垂体、海马等组织病理损伤情况,RT-PCR和Western blot法检测下丘脑、海马组织雌激素受体基因及蛋白的表达。结果与正常对照组比较,模型组大鼠糖水偏好度显著下降(P<0.01),强迫游泳不动时间显著增加(P<0.01),表现出明显抑郁样行为,血清GnRH、FSH、LH含量均显著升高(P<0.01或P<0.05),E2降低(P<0.01),下丘脑、垂体及海马组织受损,雌激素受体表达显著降低(P<0.01);经加味百合地黄汤干预治疗后,模型组大鼠抑郁样行为显著改善(P<0.01或P<0.05),HPO轴亢进状态及海马损伤得以缓解,下丘脑、海马雌激素受体表达均显著增加(P<0.01或P<0.05)。与阳性药物组比较,加味百合地黄汤高剂量组下丘脑雌激素受体基因表达显著增加(P<0.05)。结论加味百合地黄汤通过抑制HPO轴亢进及增加脑内雌激素受体水平,发挥抗围绝经期抑郁症作用。

Objective To explore the efficacy and potential mechanism of Jiawei Baihe Dihuang Decoction(JWBHDHD)in treating perimenopausal depression based on the hypothalamic-pituitary-ovarian axis(HPO axis)and estrogen receptor(ER).Methods The rats were randomized into normal control group,model group,positive drug group(1.89 mg/kg of flupentixol-melitracen solution),and high-,medium-,and low-JWBHDHD doses(16.2,8.1,4.05 g/kg)groups,with 10 rats in each group.Except the normal control group,all the other groups were established a perimenopausal depression rat model by bilateral ovariectomization combined with chronic unpredictable stress.After 21 days of administration in each group,a sugar preference test and a forced swimming test were used to evaluate the depression-like behavior of rats;enzyme-linked immunosorbent assay was used to check serum gonadotropin-releasing hormone(GnRH),follicle-stimulating hormone(FSH),luteinizing hormone(LH),and estradiol(E2)levels;HE staining was used to observe the histopathological damage of the hypothalamus,pituitary gland,and hippocampus;the expressions of estrogen receptor genes and proteins in the hypothalamus and hippocampus tissues were detected by RT-PCR and Western blot.Results Compared with the normal group,the preference for sugar water of rats in the model group significantly decreased(P<0.01),the immobility time of forced swimming significantly increased(P<0.01),and the rats in the model group showed obvious depression-like behaviors,the content of serum GnRH,FSH,and LH was significantly higher(P<0.01 or P<0.05),and E2 was lower(P<0.01).The hypothalamus,pituitary,and hippocampal tissues were damaged,and the expression of estrogen receptors was significantly lower(P<0.01).After the intervention of JWBHDHD,the depression-like behavior of model rats was significantly improved(P<0.01 or P<0.05),the hyperactivity of HPO axis and hippocampal injury were relieved,and the expression of estrogen receptor in hypothalamus and hippocampal significantly increased(P<0.01 or P<0.05).Compared with the positive drug group,the expression of estrogen receptor genes in the hypothalamus of the high-dose JWBHDHD group significantly increased(P<0.05).Conclusion JWBHDHD exerts an anti-perimenopausal depression role by inhibiting HPO axis hyperactivity and increasing estrogen receptor levels in the brain.