慢性应激抑郁模型大鼠下丘脑-垂体-肾上腺轴负反馈功能与蒙药槟榔十三味丸的干预

摘要

BACKGROUND:Mongolian Pharmaceutical Betel Shisanwei Ingredients Pil has achieved good clinical efficacy, but the underlying mechanism remains unclear. OBJECTIVE: To study the effects of Mongolian Pharmaceutical Betel Shisanwei Ingredients Pil on the hypothalamic-pituitary-adrenal axis negative feedback function in the chronic depressed rats, and to explore anti-depression mechanisms of Mongolian Pharmaceutical Betel Shisanwei ingredients pil. METHODS: Eighty male Wistar rats were randomly divided into ten groups according to the sugar consumption test (with eight rats in each group): normal control group, model group, fluoxetine group, high-, medium- and low-dose Betel Shisanwei Ingredients Pil groups, RU486 group, high-, medium- and low-dose Betel Shisanwei Ingredients Pil plus RU486 groups. Except normal control group, the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely rising, to establish depression models. In the meantime, rats of the high-, medium- and low-dose Betel Shisanwei Ingredients Pil groups were given oral gavage of Betel Shisanwei Ingredients Pil (0.2, 0.4, 0.8 g/kg) for 28 days; rats of the normal control group and model group were intragstricaly administered with sodium carboxymethyl celulose; rats of RU486 group were given abdominal subcutaneous injection of RU486 from day 21 after modeling; rats of the high-, medium- and low-dose Betel Shisanwei Ingredients Pil plus RU486 groups were intragstricaly administered with Betel Shisanwei Ingredients Pil (0.2, 0.4, 0.8 g/kg) and subcutaneous injection of RU486 from day 21. RESULTS AND CONCLUSION:Compared with normal control group, cortisone content increased significantly (P < 0.05), the expression of glucocorticoid receptor mRNA in hippocampus, hypothalamus and pituitary gland decreased significantly, and hypothalamic corticotrophin releasing hormone mRNA expression increased significantly in the model group and RU486 group. Compared with model group, cortisone content decreased, the expression of glucocorticoid receptor mRNA in hippocampus, hypothalamus and pituitary gland increased significantly, and hypothalamic corticotrophin releasing hormone mRNA expression decreased significantly in rats treated with Betel Shisanwei Ingredients Pil. Compared with RU486 group, Betel Shisanwei Ingredients Pil administration led to changed in cortisone content, glucocorticoid receptor mRNA expression in hippocampus, hypothalamus and pituitary gland, as wel as hypothalamic corticotrophin releasing hormone mRNA expression. Experimental findings indicate that, Betel Shisanwei Ingredients Pil can directly regulate excessive secretion of glucocorticoid, and improve the dysfunction of hypothalamic-pituitary-adrenal axis central negative feedback through increasing glucocorticoid receptor mRNA expression and decreasing corticotropin releasing hormone mRNA expression. After the hypothalamic-pituitary-adrenal axis negative feedback pathway is blocked, the effect of Betel Shisanwei Ingredients Pil is weakened.%背景：抑郁症是具有很高的致死、致残率，严重威胁着人类健康的常见精神疾患。临床上应用槟榔十三味丸治疗抑郁症取得良好的疗效。但其作用机制尚未明确。目的：观察蒙药槟榔十三味丸对慢性应激抑郁模型大鼠下丘脑-垂体-肾上腺轴负反馈功能的影响，探讨槟榔十三味丸抗抑郁作用机制。方法：80只Wistar雄性大鼠，根据蔗糖水消耗量随机分为正常对照组、模型组、氟西汀组、槟榔十三味丸低、中、高剂量组、RU486组和槟榔十三味丸低、中、高剂量+RU486组，每组8只。除正常对照组外，其余大鼠均采用慢性应激结合孤养方法制备抑郁模型，槟榔十三味丸低、中、高剂量组大鼠在造模同时连续28 d灌胃槟榔十三味丸0.2，0.4，0.8 g/kg；正常对照组和模型组大鼠灌胃羧甲基纤维素钠；RU486组大鼠自造模第21天起腹部皮下注射糖皮质激素受体拮抗剂RU486；槟榔十三味丸低、中、高剂量+RU486组大鼠在造模同时灌胃槟榔十三味丸0.2，0.4，0.8 g/kg，且自造模第21天起腹部皮下注射RU486。结果与结论：与正常对照组相比，模型组及RU486组大鼠肾上腺皮质酮水平显著升高(P <0.05)，海马、下丘脑、垂体糖皮质激素受体mRNA表达显著下降，下丘脑促肾上腺皮质激素释放激素mRNA表达显著增多；与模型组相比，灌胃槟榔十三味丸的大鼠肾上腺皮质酮水平降低，海马、下丘脑、垂体糖皮质激素受体mRNA表达明显增多，下丘脑促肾上腺皮质激素释放激素mRNA表达水平显著降低；且与RU486组相比，同时灌胃槟榔十三味丸的大鼠肾上腺皮质酮、海马、下丘脑、垂体糖皮质激素受体 mRNA、下丘脑促肾上腺皮质激素释放激素mRNA表达水平也出现改变。提示槟榔十三味丸对糖皮质激素的过度分泌有直接的调控作用，并可通过增强糖皮质激素受体mRNA的表达及降低促肾上腺皮质激素释放激素mRNA的表达，改善下丘脑-垂体-肾上腺轴负反馈中枢的功能障碍。当下丘脑-垂体-肾上腺轴负反馈通路被阻断后，槟榔十三味丸作用减弱。