Alterations in hypothalamic-pituitary-adrenal/thyroid (HPA/HPT) axes correlated with the clinical manifestations of depression

The alterations of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are important neuroendocrine abnormalities in depression. We aimed to identify some potential associations between these alterations and the clinical manifestations of depression in a sample of Chinese origin. 565 depressed patients of Chinese Han region were collected and seven kinds of hormones in HPA and HPT axes were detected. A 17-item Hamilton Depression Rating Scale (HAMD-17) and a 14-item Hamilton Anxiety Rating Scale (HAMA-14) were used to evaluate the baseline condition of each patient. 519 patients were enrolled into analysis. The patients with dysfunction of HPA axis had susceptibility to agitation symptoms (HAMD9 item) and cognitive disorders (HAMD2, 3 and 9 items), while those with normal function of HPA axis had susceptibility to shallow sleep (HAMD5 item). The patients with dysfunction of HPT axis had susceptibility to difficulty in falling asleep (HAMD4 item), weight loss (HAMD16 item) and gastrointestinal symptoms (HAMD12 item). Besides, the patients with dysfunctions of both HPA and HPT axes showed remarkable retardation symptoms (HAMD8 item). These findings might provide some evidences for the clinical subgrouping and management individualization of depressed patients according to the neuroendocrine alterations.     

CRH家族肽参与免疫调节的信号转导机制研究进展

几乎所有的免疫组织和器官都表达CRH家族肽成员,它们可通过与其受体(CRHR1和CRHR2)结合以自分泌或旁分泌方式参与机体免疫细胞功能调节的过程.其中CRH与UCN是目前研究最多的两种CRH家族肽成员,对免疫细胞功能的调节机制与cAMP-PKA、核转录因子、PKC和MAPK、钙离子信号等有关,其作用存在着组织的特异性和差异性,在不同的组织可产生不同的效应.     

脑缺血再灌注对大鼠下丘脑-垂体-肾上腺-胸腺轴的影响

为探讨脑缺血再灌注损伤对大鼠神经-内分泌和免疫功能的影响,本研究采用免疫组织化学和放射免疫等实验技术,从形态、结构和功能三个层次观察了脑缺血再灌注损伤时大鼠下丘脑-垂体-肾上腺-胸腺(HPAT)轴的变化。结果发现:脑缺血后6h、9h组大鼠垂体重量明显减轻;其下丘脑和垂体激素分泌细胞数量减少,体积缩小;脑缺血后血浆CRH、ACTH和CORT浓度呈一致性先短暂升高后持续下降,T细胞增殖能力、T细胞克隆形成率和IL-2活性明显下降,且上述改变缺血9h组重于6h组。当脑缺血恢复再灌注时,缺血3h再灌注组比缺血6h再灌注组恢复快。以上结果表明:①脑缺血再灌注时,HPAT轴先出现一短暂的激活过程,继而很快转入抑制状态;②脑缺血再灌注损伤后大鼠免疫功能受抑制;③缺血后恢复再灌注早,HPAT轴受损轻,恢复快。     

An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation

The gender difference in behavioral and hormonal response to stress is well known, but the underlying mechanism remains elusive. Arginine-vasopressin (AVP) and corticotrophin-releasing hormone (CRH) are two major regulatory peptides in the brain involved in stress regulation. Their response to stress has been shown to be modulated by sex hormones. The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol (3beta-diol), has been identified as an estrogenic hormone. It binds to estrogen receptors (ERs) and modulates estrogen response element mediated promoter activities via the ER pathway. The present study involved in vitro transfection assays to examine whether 3beta-diol can directly modulate CRH and AVP promoter activity. Our results demonstrate that in CHO-K1 cell lines, when ERs were over-expressed, 3beta-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway. The effect of 3beta-diol on the behavioral, the CRH and the AVP response to stress in the rat was also investigated. We found that chronic, but not acute administration of 3beta-diol significantly decreased the immobile duration in the forced swim test. In rats exposed to the forced swim test, CRH mRNA expression in the hypothalamus was enhanced by chronic 3beta-diol administration, while the AVP mRNA expression was not affected. These results suggest that 3beta-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.     

Median eminence nitric oxide signaling

It is becoming increasingly clear that nitric oxide (NO), an active free radical formed during the conversion of arginine to citrulline by the enzyme NO synthase (NOS), is a critical neurotransmitter and biological mediator of the neuroendocrine axis. Current evidence suggests that NO modulates the activity of both the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis. Supporting this hypothesis is the finding that the highest expression of neuronal NOS in the brain is found within the hypothalamus in areas where the cell bodies of the neurons from the different neuroendocrine systems are located. In this regard, the influence of neuronal NO on the regulation of the neuroendocrine neural cell body activity has been well-documented whereas little is known about NO signaling that directly modulates neurohormonal release into the pituitary portal vessels from the neuroendocrine terminals within the median eminence, the common termination field of the adenohypophysiotropic systems. Studies in rat suggest that NO is an important factor controlling both gonadotropin-releasing hormone (GnRH) and corticotropin-releasing hormone (CRH) release at the median eminence. The recent use of amperometric NO detection from median eminence fragments coupled to the use of selective NOS inhibitors demonstrated that a major source of NO at the median eminence might be endothelial in origin rather than neuronal. The present article reviews the recent progress in identifying the origin and the role of the NO produced at the median eminence in the control of neurohormonal release. We also discuss the potential implications of the putative involvement of the median eminence endothelial cells in a neurovascular regulatory process for hypothalamic neurohormonal signaling.     

E2、P、CRH在早产发病中的作用

目的观察妊娠晚期孕妇外周血中雌二醇(E2)、孕酮(P)、促肾上腺皮质激素释放激素(corticotropin-releasing hor-mone,CRH)的变化及其在早产发病中的作用和它们之间的相互关系。方法选取正常妊娠组孕妇60例,先兆早产组孕妇63例(早产组21例,继续妊娠组42例),采集外周静脉血分离血浆,用免疫化学发光法测定E2、P,放射免疫法测定CRH水平。结果1)妊娠晚期正常孕妇血中的CRH质量浓度随着孕周增加而逐渐升高,而血E2质量浓度无明显变化,P质量浓度31~32周达到高峰,之后明显下降。2)正常妊娠组和先兆早产组各孕周组间血CRH、P比较差异均有统计学意义(P<0.01),而正常妊娠组和先兆早产组妊娠29~30周和31~32周2个孕周组间血E2比较差异无统计学意义(P>0.05),妊娠33~34周和35~36周2孕周组间比较差异有统计学意义(分别为P<0.01和P<0.05)。3)早产组CRH、E2显著高于继续妊娠组,差异有统计学意义(P<0.01)。早产组P显著低于继续妊娠组,差异有统计学意义(P<0.05)。结论1)CRH可能是分娩发动的重要因素。2)CRH在早产发病中起重要作用,CRH的异常升高可能决定了分娩时间的提前。监测孕妇血CRH的变化有望成为预测早产的可靠指标。3)与E2相比,P在早产发动中发挥更重要的作用。     

Involvement of dopamine system in the regulation of the brain corticotropin-releasing hormone in paraventricular nucleus in a rat model of chronic visceral pain

Objective We aimed to investigate the mechanism of paraventricular nucleus (PVN) and ventral tegmental area (VTA) circuit in the pathogenesis of visceral pain-depression with a rat model induced by neonatal and adult colorectal distension (CRD).

Methods Neonate male Sprague-Dayley (SD) rats underwent CRD on postnatal days 8, 10, and 12, and when matured, were tested for adult abdominal withdrawal reflex (AWR) scores to assess visceral hypersensitivity. The forced swimming test was employed to evaluate depression-like behaviors. The rats exhibiting visceral pain-depressive behaviors underwent lidocaine injection in the VTA to explore the relationship between VTA and visceral pain. Moreover, double immunofluorescence was employed to evaluate the qualitative and quantitative expression of dopamine/ c-Fos in CRD rats. After verifying the existed fiber projection from PVN to VTA, the intra-PVN microinjection of CRH-RNAi lentivirus to inhibit corticotropin-releasing hormone (CRH) expression, behavioral changes were assessed by AWR score and FST. Thereafter, with the sacrifice of the rats, the variations of TH protein in rats were evaluated by immunofluorescence and Western blot.

Results Intra-VTA microinjection of lidocaine increased the pain threshold of CRD group. After intra-VTA microinjection of green retrograde tracer, immunofluorescence photomicrographs visualized the PVN with a typical green retrograde tracer. Intra-PVN microinjection of CRH-RNAi lentivirus alleviated the visceral pain-depression behaviors and decreased the TH protein expression in the VTA.

Conclusion These data demonstrated that the VTA played a functional role in chronic visceral pain and depression, and the CRH-containing neurons in hypothalamic PVN may be implicated in the onset and maintenance of the chronic visceral pain and depression via the activation of dopamine in the VTA.     

大鼠胸部严重创伤后早期下丘脑CRH表达的实验研究

目的 探讨大鼠胸部撞击伤应激反应中,下丘脑表达和分泌促肾上腺皮质激素释放激素(CRH)的变化规律及其反馈调节机制。方法 应用BIM-Ⅲ型多功能小型生物撞击机致伤动物,采用免疫组化和RT-PCR等技术,检测大鼠下丘脑CRH的分布及含量变化规律。分组：对照组、撞击伤后15、30、60、120、360、720分钟组、撞击伤处理组(用CRH1R特异性阻滞剂CP-154526处理)。结果 正常情况下,CRH少量分布于下丘脑室旁核和视上核;撞击伤后,室旁核和视上核的CRH染色明显增加;撞击伤后60分钟,下丘脑CRH mRNA含量明显增加,且呈逐渐增加的趋势,720分钟开始回落;用CP-154526处理的大鼠,撞击伤后,下丘脑CRH含量的增加明显减少。结论 在创伤性应激反应早期,CRH通过与下丘脑神经元CRH1R的结合,选择性地调节下丘脑神经元CRH基因的表达。     

Evidence that PGE2 in the dorsal and median raphe nuclei is involved in LPS-induced anorexia in rats

Anorexia is an element of the acute-phase immune response. Its mechanisms remain poorly understood. Activation of inducible cyclooxygenase-2 (COX-2) in blood-brain-barrier endothelial cells and subsequent release of prostaglandins (e.g., prostaglandin E2, PGE2) may be involved. Therefore, we sought to relate the effects of prostaglandins on the anorexia following gram-negative bacterial lipopolysaccharide treatment (LPS) to neural activity in the dorsal and median raphe nuclei (DRN and MnR) in rats. COX-2 antagonist (NS-398, 10 mg/kg; IP) administration prior to LPS (100 μg/kg; IP) prevented anorexia and reduced c-Fos expression the DRN, MnR, nucleus tractus solitarii and several related forebrain areas. These data indicate that COX-2-mediated prostaglandin synthesis is necessary for LPS anorexia and much of the initial LPS-induced neural activation. Injection of NS-398 into the DRN and MnR (1 ng/site) attenuated LPS-induced anorexia to nearly the same extent as IP NS-398, suggesting that prostaglandin signaling in these areas is necessary for LPS anorexia. Because the DRN and MnR are sources of major serotonergic projections to the forebrain, these data suggest that serotonergic neurons originating in the midbrain raphe play an important role in acute-phase response anorexia.     

养正胶囊制备工艺研究

目的研究养正胶囊适宜辅料及制备工艺。方法以颗粒的休止角、粒度、堆密度以及颗粒的吸湿性曲线和颗粒的CRH为考察指标,筛选出合适的辅料及最佳制备工艺。结果颗粒的CRH为62.5%,颗粒质量适合生产。结论该工艺切实可行,适于工业化大生产。