熊果酸改善慢性温和不可预知应激小鼠抑郁行为的研究
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摘要
目的研究熊果酸改善慢性温和不可预知应激抑郁模型(CUMS)小鼠行为及下丘脑-垂体-肾上腺轴(HPA)轴功能失调的作用。方法 ICR小鼠接受温和不可预知刺激,28 d后经糖水偏好实验评价模型,分组:CUMS组、熊果酸干预组(灌胃,5、10、20 mg/kg)和氟西汀阳性对照组(灌胃,5 mg/kg),同时设置正常组。给药持续21 d,最后1周进行糖水偏好实验、矿场试验和强迫游泳实验,评价熊果酸对CUMS小鼠抑郁行为的影响,并检测血清促肾上腺皮质激素和皮质酮及海马糖皮质激素受体蛋白水平的变化,评价HPA轴功能。结果熊果酸增加CUMS小鼠体重(P<0.01,P<0.001),提高小鼠糖水偏好值(P<0.05,P<0.01)和自主运动时间(水平:P<0.01,P<0.001;垂直:P<0.01,P<0.01),并降低强迫游泳不动时间(P<0.05,P<0.01)。熊果酸还能降低血清促肾上腺皮质激素(P<0.05)和皮质酮水平(P<0.05),增加海马糖皮质激素受体蛋白表达(P<0.01)。氟西汀也能抑制CUMS小鼠的抑郁行为和HPA轴的异常变化,其作用效果与高剂量熊果酸的相当。结论熊果酸具有抗抑郁作用,其机制可能与抑制HPA轴的亢进相关。
Objective To investigate the antidepressant-like activity of ursolic acid, and explore its mechanism related to hypothalamic-pituitary-adrenal(HPA) axis in mice exposed to chronic mild unpredictable stress(CUMS). Methods Mice were subjected to 28 days of CUMS. During the last 21 days, mice in the ursolic acid groups were treated with oral ursolic acid of 5, 10, 20 mg/kg, respectively, and the control group was treated with 5 mg/kg fluoxetine. Sucrose preference, openfield test and forced swimming test(FST) were used to evaluate the antidepressant effects of ursolic acid in CUMS model.Changes in serum adrenocorticotropic hormone(ACTH) and corticosterone, and the expression of hippocampal glucocorticoid receptor(GR) were measured to evaluate the activation of HPA axis. Results Our findings indicated that ursolic acid caused change inthe body weight, sucrose preferences, locomotor activities and immobility time in FST of the CUMS mice. In addition, ursolic acid reduced the abnormalities of the ACTH and corticosterone levels in serum, and increased GR expression in hippocampus. Fluoxetine also normalized the body weight, sucrose preferences, locomotor activities and immobility time in FST and inhibited the hyperactivity of HPA axis of the CUMS mice. The efficacy of 20 mg/kg ursolic acid is comparable with that of 5 mg/kg fluoxetine. Conclusion The antidepressant effects of ursolic acid may be related to the suppression hyperactivity of the HPA axis in CUMS model.
Objective To investigate the antidepressant-like activity of ursolic acid, and explore its mechanism related to hypothalamic-pituitary-adrenal(HPA) axis in mice exposed to chronic mild unpredictable stress(CUMS). Methods Mice were subjected to 28 days of CUMS. During the last 21 days, mice in the ursolic acid groups were treated with oral ursolic acid of 5, 10, 20 mg/kg, respectively, and the control group was treated with 5 mg/kg fluoxetine. Sucrose preference, openfield test and forced swimming test(FST) were used to evaluate the antidepressant effects of ursolic acid in CUMS model.Changes in serum adrenocorticotropic hormone(ACTH) and corticosterone, and the expression of hippocampal glucocorticoid receptor(GR) were measured to evaluate the activation of HPA axis. Results Our findings indicated that ursolic acid caused change inthe body weight, sucrose preferences, locomotor activities and immobility time in FST of the CUMS mice. In addition, ursolic acid reduced the abnormalities of the ACTH and corticosterone levels in serum, and increased GR expression in hippocampus. Fluoxetine also normalized the body weight, sucrose preferences, locomotor activities and immobility time in FST and inhibited the hyperactivity of HPA axis of the CUMS mice. The efficacy of 20 mg/kg ursolic acid is comparable with that of 5 mg/kg fluoxetine. Conclusion The antidepressant effects of ursolic acid may be related to the suppression hyperactivity of the HPA axis in CUMS model.
引文
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[14]Wang M,Chen Q,Li M,et al.Alarin-induced antidepressant-like effects and their relationship with hypothalamus-pituitary-adrenal axis activity and brain derived neurotrophic factor levels in mice[J].Peptides,2014,56:163-172.
[2]Swaab DF,Bao AM,Lucassen PJ.The stress system in the human brain in depression and neurodegeneration[J].Ageing Research Reviews,2005,4(2):141-194.
[3]He XS,Ma N,Pan ZL,et al.Functional magnetic resource imaging assessment of altered brain function in hypothyroidism during working memory processing[J].European journal of endocrinology/European Federation of Endocrine Societies,2011,164(6):951-959.
[4]Ge JF,Gao WC,Cheng WM,et al.Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress[J].European neuropsychopharmacology:the journal of the European College of Neuropsychopharmacology,2014,24(1):172-180.
[5]Cai L,Li R,Tang WJ,et al.Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis[J].European neuropsychopharmacology:the journal of the European College of Neuropsychopharmacology,2015,25(8):1332-1341.
[6]Machado DG,Neis VB,Balen GO,et al.Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L.in mice:evidence for the involvement of the dopaminergic system[J].Pharmacology Biochemistry and Behavior,2012,103(2):204-211.
[7]Colla AR,Oliveira A,Pazini FL,et al.Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice[J].Pharmacology Biochemistry and Behavior,2014,124:108-116.
[8]Willner P,Towell A,Sampson D,et al.Reduction of sucrose preference by chronic unpredictable mild stress,and its restoration by a tricyclic antidepressant[J].Psychopharmacology,1987,93(3):358-364.
[9]Porsolt RD,Bertin A,Jalfre M.Behavioral despair in mice:a primary screening test for antidepressants[J].Archives internationales de pharmacodynamie et de therapie,1977,229(2):327-336.
[10]Romer B,Lewicka S,Kopf D,et al.Cortisol metabolism in depressed patients and healthy controls[J].Neuroendocrinology,2009,90(3):301-306.
[11]Brown ES.Effects of glucocorticoids on mood,memory,and the hippocampus.Treatment and preventive therapy[J].Annals of the New York Academy of Sciences,2009,1179:41-55.
[12]Schüle C,Baghai TC,Eser D,et al.Hypothalamic-pituitary-adrenocortical system dysregulation and new treatment strategies in depression[J].Expert Review of Neurotherapeutics,2009,9(7):1005-1019.
[13]Li YC,Shen JD,Li YY,et al.Antidepressant effects of the water extract from Taraxacum officinale leaves and Roots in mice[J].Pharmaceutical Biology,2014,52(8):1028-1032.
[14]Wang M,Chen Q,Li M,et al.Alarin-induced antidepressant-like effects and their relationship with hypothalamus-pituitary-adrenal axis activity and brain derived neurotrophic factor levels in mice[J].Peptides,2014,56:163-172.