Study On The Antidepressant Role Of Estrogen's Co-factors And Their Mechanisms

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.