抑郁症中芳香化酶的变化：死亡后人脑样本研究和动物学研究

发布时间：2018-11-19 17:47

【摘要】：目的:大量证据显示,下丘脑-垂体-肾上腺(hypothalamo-pituitary-adrenal,HPA)轴活性过度亢进是抑郁症的重要神经生物学发病机制。下丘脑室旁核(paraventricular nucleus,PVN)内促肾上腺皮质激素释放激素(corticotropin-releasing hormone,CRH)是HPA轴活性的中枢驱动因子,在抑郁症中PVN内CRH分泌显著增加是HPA轴活性亢进的重要基础。我们和其他组之前的研究发现,性激素,包括雌激素和雄激素可以通过各自的核受体调控CRH基因的表达。雌激素促进,而雄激素抑制CRH基因表达;此外,在抑郁症患者发现,下丘脑内CRH活性升高伴随着雌激素受体表达上调而雄激素受体表达下调。这些数据提示,抑郁症患者下丘脑中可能发生了雌、雄激素水平之间平衡紊乱,并可能对HPA轴活性过度激活起到重要作用。芳香化酶是体内包括脑内介导雄激素向雌激素转化的关键限速酶。我们的假说是,抑郁症患者下丘脑PVN内芳香化酶活性可能发生了不适当的过度激活。因此,我们在重性抑郁障碍(major depressive disorder,MDD)患者研究了下丘脑PVN内芳香化酶的表达。令人惊讶的是,我们发现MDD患者PVN内芳香化酶表达显著减低。我们继而在大鼠抑郁症模型研究了抑制芳香化酶活性对大鼠应激反应相关激素以及抑郁样行为的影响。方法:(1)针对死亡后人脑样本的研究:在10名MDD患者和与之严格匹配的10名对照者下丘脑PVN内,采用定量免疫细胞化学方法检测芳香化酶表达水平。组间匹配因素包括:性别、年龄、死亡时间、死亡季节、死亡后延搁时间、标本固定时间等。(2)针对抑郁症大鼠模型,给予芳香化酶抑制剂的研究:在雄性SD大鼠皮下植入含有芳香化酶抑制剂1,4,6-雄三酮-3,17-二酮(1,4,6-androstatriene-3,17-dione,ATD)胶囊(ATD)或者空胶囊(sham),给予慢性不可预见性轻度应激(chronic unpredictable mild stress,CUMS)或者无应激作为对照(control)。大鼠共分为四组:control-sham 组、CUMS-sham 组、control-ATD组、CUMS-ATD组。研究ATD对抑郁样行为包括糖水偏好行为学实验、强迫游泳实验中的行为,以及对相关应激激素包括血浆皮质酮、睾酮、雌二醇以及下丘脑性甾体睾酮和雌二醇水平的影响。结果:(1)抑郁症患者下丘脑PVN内芳香化酶免疫反应性显著下降(P=0.029)。(2)CUMS组大鼠体重(F=18.686,P0.001)和糖水偏好(F=44.379,P0.001)显著低于对照组,而强迫游泳实验中不动时间(F= 44.379,P0.001)显著长于对照组;CUMS组大鼠血浆皮质酮(F=40.908,P0.001)显著高于对照组;ATD组大鼠血浆(F=7.501,P=0.011)和下丘脑中睾酮(F = 6.741,P=0.016)水平显著增加而雌二醇水平无明显改变;ATD给药显著增加大鼠血浆(P=0.005)和下丘脑(P= 0.055)的睾酮/雌二醇的比率;但是,ATD对血浆CORT水平、糖水偏好行为、强迫游泳行为相关指标无显著影响。结论:成年期下丘脑内芳香化酶的活性改变没有对抑郁症发病机制发挥重要影响。根据我们的研究发现和文献,我们推测发育期脑内芳香化酶活性改变可能参与了抑郁症发病机制,该假说值得进一步研究确认。
[Abstract]:Objective: A large amount of evidence shows that hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis is an important neurobiological mechanism of depression. The corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus is the central driving factor of the activity of the HPA axis, and the significant increase of the CRH secretion in the PVN in the depression is an important basis for the hyperactivity of the HPA axis. We and other groups have found that sex hormones, including estrogen and androgens, can modulate the expression of the CRH gene by their respective nuclear receptors. in addition, in depression, that increase in CRH activity in the hypothalamus is accompanied by an increase in the expression of the estrogen receptor and down-regulation of the androgen receptor. These data suggest that there may be an imbalance between the levels of estrogen and androgen in the hypothalamus of patients with depression, and may play an important role in the excessive activation of HPA axis activity. Aromatase is a key speed-limiting enzyme that includes in-vivo brain-mediated androgen-to-estrogen transformation. Our hypothesis is that the activity of the aromatase in the PVN in the hypothalamus of patients with depression may have been unduly overactivated. Therefore, we study the expression of the aromatase in the hypothalamic PVN in the patients with major depressive disorder (MDD). Surprisingly, we found that the expression of aromatase in PVN was significantly reduced in patients with MDD. We then study the effect of inhibiting aromatase activity on stress-related hormone and depression-like behavior of rats in the rat model of depression. Methods: (1) The expression level of aromatase was detected by quantitative immunocytochemical method in 10 patients with MDD and 10 controls. The inter-group matching factors included sex, age, time of death, the time of death, the time after death, the fixed time of the specimen, etc. (2) An aromatase inhibitor was administered to a depression rat model: an aromatase inhibitor 1, 4, 6-androstatin-3,17-dione (ATD) capsule (ATD) or an empty capsule (sham) was implanted subcutaneously in male SD rats, Chronic unpredictability mild stress (CUMS) or no stress was given as a control. The rats were divided into four groups: control-sham group, CUMS-sham group, control-ATD group and CUMS-ATD group. The effects of ATD on the behavior of depression-like behavior, including carbohydrate-water-preference behavior, forced swimming, and the level of serum corticosterone, testosterone, estradiol and the level of testosterone and estradiol in the hypothalamus, were studied. Results: (1) The immunoreactivity of the aromatase in the PVN in the hypothalamus of the patients with depression (P = 0.029). (2) The weight of rats in the CUMS group (F = 18. 686, P 0.001) and the preference of sugar water (F = 44. 379, P 0.001) were significantly lower than that of the control group (F = 44. 379, P 0.001). The plasma corticosterone (F = 40. 908, P. 001) in the CUMS group was significantly higher than that in the control group, and the plasma of the rats in the ATD group (F = 7.501, P 0.001) was significantly higher than that of the control group. The levels of testosterone (F = 6.741, P = 0.016) in the hypothalamus (P = 0.011) and in the hypothalamus were significantly increased and the level of estradiol was not significantly changed; ATD administration significantly increased the ratio of testosterone/ estradiol in the rat plasma (P = 0. 005) and the hypothalamus (P = 0. 055); however, ATD was responsible for plasma CORT level, sugar water preference behavior, There was no significant effect on the related indexes of forced swimming. Conclusion: The changes of the activity of the aromatase in the hypothalamus did not play an important role in the pathogenesis of depression. According to our findings and literature, we have speculated that the changes in the activity of aromatase in the brain of the developmental stage may be involved in the pathogenesis of depression, which is worthy of further study and confirmation.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.4

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