摘要
抑郁症是一种常见的精神疾病,其发病原因被认为是基因与环境相互作用的结果,但具体的致病因素至今尚不能确定。在数十年来对抑郁症发病机制的研究中,科学家们提出了许多种假说,其中包括单胺类递质假说、神经内分泌假说、神经再生障碍假说等等。而恰恰这些假说的物质基础都与甾类激素尤其是雌激素有着密不可分的联系。例如,单胺类假说中5-羟色胺系统就受到雌激素的调控,神经内分泌假说的下丘脑—垂体—肾上腺(HPA)轴活性调控和性激素介导的下丘脑—垂体—性腺(HPG)轴,更是有着紧密的交互作用。通过研究激素对下丘脑-垂体-肾上腺轴的调控作用,我们可以进一步了解激素及其受体在生物体的应激反应中的功能,以及在抑郁症发病机制和治疗之中起到的重要作用。本文利用大鼠强迫游泳抑郁模型和启动子活性分析等一系列方法,探讨了雌激素对HPA轴的调控作用及其与组蛋白去乙酰化抑制剂(HDACi)协同的抗抑郁效应。并进一步通过对HPA轴和5-羟色胺系统的研究探讨了该协同作用的可能机制。
1、近来研究发现组蛋白乙酰化酶抑制剂,丁酸钠,有可能具有一定的抗抑郁效应。并与选择性5-羟色胺再摄取抑制剂(SSRI)具有协同作用。众所周知,雌激素与SSRI,例如氟西汀(Fluoxetine),之间也存在协同的抗抑郁效应。然而雌激素在丁酸钠的抗抑郁作用中有什么样的作用我们不得而知。本实验中,我们使用大鼠强迫游泳的模型研究了去势雌性大鼠丁酸钠与雌激素共给药的抗抑郁作用。为了进一步研究其可能的机制,我们对下丘脑的5-羟色胺系统以及HPA轴系统进行了mRNA表达的分析。我们知道这两者在抑郁症发病机制及治疗中起重要的作用。去势的雌性SD大鼠分为对照组、丁酸钠组、雌激素组和共给药组四个组。连续给药七天之后进行强迫游泳检测,并利用实时定量PCR的方法研究下丘脑的目的基因的mRNA表达。结果发现共给药组不动时间显著低于对照组,当在检测前30分钟给以5-羟色胺1A受体抑制剂,WAY 100 635之后,共给药的效应完全被阻断。进一步的定量PCR结果显示下丘脑5-羟色胺1A受体的mRNA显著增高。结果提示我们在大鼠强迫游泳的模型中,5-羟色胺1A受体参与了丁酸钠和雌激素协同的抗抑郁作用,下丘脑5-羟色胺1A受体mRNA的表达变化提示下丘脑的5-羟色胺1A受体可能参与其中。
2、人促肾上腺皮质激素释放激素(CRH)在应激反应和抑郁症的发病机制中扮演着重要的角色,其表达受到诸如雌激素等甾类激素的调控。最近人们发现雌激素受体的转录活性受到泛素类似蛋白(SUMO)1修饰的影响。本实验采用CHO-K1细胞系瞬时转染人雌激素受体和SUM01进行CRH启动子活性分析的方法,研究SUM01对雌激素受体调控CHR启动子活性的影响。我们发现雌激素通过雌激素受体激活CRH的转录,SUM01极大的促进了雌激素对CRH的激活作用,雌激素受体拮抗剂ICI 182 780能够将其完全阻断。我们的结果提示雌激素通过雌激素受体调控CRH的表达,而SUM01参与了雌激素受体对CRH的调控。
Major depression is well known as a mental disorder,which is believed to result from the synergic action of genes and environment.However, the key factor remains unclear.Decades of research came up with several hypothesis,such as monoamine,neuroendocrinology,neural regeneration and so on,all of which are closely correlated to sex hormones.For example, serotonergic system is under the regulation of sex hormones.Increasing evidence showed the interaction of the HPA axis and the HPG axis.Through studying the regulatory action of estrogen on HPA axis activity,we could reveal the functions of sex hormones and their receptors in the stress system and even in the pathological and therapeutic mechanisms of depression.In our present study,by rat forced swimming test and promoter activity analysis,we investigated the effects of estrogen on HPA axis and the antidepressant-like effects in combination with histone deacetylase inhibitor(HDACi).We uncovered the possible mechanisms by monitoring the alteration the HPA axis and the serotonergic systems.
1、Sodium butyrate(NAB),a histone deacetylase inhibitor,has been implicated in the antidepressant-like effects either injected as a single drug or in combination with selective serotonin reuptake inhibitor(SSRI), such as fluoxetine.Estrogen is also demonstrated to have antidepressant effect especially together with fluoxetine.We investigated whether NaB administered in combination with estradiol benzoate(EB) exerted antidepressant-like effect in forced swimming test(FST) in ovariectomized female rats.Furthermore,we detected the mRNA expressions of serotonin receptors and neuropeptides in hypothalamus, both of which participate in the mood disorder.Ovariectomized female SD rats were treated with vehicle,NaB,EB or NaB combined with EB for 7 days and then subjected to FST.The expressions of serotonin receptors (5-hydroxytryptamine receptor),corticotropin-releasing hormone(CRH) and arginine vasopressin(AVP) mRNA in the hypothalamus were detected by real time PCR.We found that co-treated with NaB and EB resulted in a significant decrease in immobility behavior in FST,a measure for depression-like behavioral.5-HT1A antagonist,WAY 100635, significantly block the antidepressant-like effects induced by NaB plus EB.The mRNA expression of the serotonin-1A[5-hydroxytryptamine 1A (5-HT1A)]receptor was increased in the co-treated group in hypothalamus, while there was no difference in the mRNA expression of 5-HT2A or 5-HT2C. The mRNA expression of CRH or AVP was not significantly altered either. In conclusion,NaB may exert antidepressant-like effects in combination with EB in ovariectomized female rats through 5-HT1A receptor,via altering the expression of 5-HT1A in the hypothalamus.
2、Human corticotrophin-releasing hormone(CRH) plays a pivotal role in the stress response.Its expression is under the control of various steroid hormones,such as estrogens.The transcriptional activity of the estrogen receptor(ER) may be modified by small-ubiquitin related modifier(SUMO1).In the present study,we aim to reveal the role of SUMO1 in the regulation of ER-mediated CRH promoter activation.CHO-K1 cells were transfected with human ER and SUMO1 expressing plasmids together with the CRH promoter reporter gene.CRH mRNA was detected in BE(2)C cells by real time PCR.We found that estradiol could elevate CRH promoter activity to a much higher level in cells co-transfected with ER and SUMO1 than that with ER alone,and that the enhancement was blocked by the ER inhibitor,ICI182,780.Furthermore,the endogenous CRH mRNA expression was also increased when the BE(2)C cell were transfected with ERαand SUMO1 in contrast to the transfection with ERαalone.Our results indicate that SUMO1 participates in the modulation of ER-mediated CRH mRNA expression which may be important for the regulation of the stress response.
引文
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