Anti-anxiety effect of Valeriana jatamansi Jones extract via regulation of the hypothalamus-pituitary-adrenal axis

BACKGROUND： Hypothalamus-pituitary-adrenal （HPA） axis dysfunction has been closely linked to anxiety. Previous studies have shown that Valeriana jatamansi Jones extract exhibits clear anxiolytic effects, but it is unclear about the mechanism underlying regulation of the HPA axis dysfunction in these anxiolytic effects. OBJECTIVE： To observe the effects of Valeriana jatamansi Jones （Zhizhu Xiang） extract on HPA axis function in a rat model of anxiety, and to compare these effects with positive control estazolam. DESIGN, TIME AND SETTING： Randomized, controlled, animal experiment was performed at Chengdu University of Traditional Chinese Medicine, China, between February and September in 2006. MATERIALS： Estazolam was purchased from Shanghai Jiufu Pharmaceutical, China; Valeriana jatamansiJones was purchased from the Lotus Pond Market for Chinese Herbal Medicine in Chengdu. It consisted of iridoids and flavonoid components. METHODS： A total of 72 Sprague Dawley rats, aged 2 months, were randomly assigned to 6 groups low-, medium-, and high-dose Valerianajatamansi Jones groups intragastrically injected with 0.3, 0.6, and 0.9 g/kg per day Valerianajatamansi Jones extract, respectively; estazolam group intragastrically injected with 1.5 mg/kg per day estazolam; model and normal groups administered 5 mL physiological saline. Anxiety was established in all groups, except the normal group, through the use of elevated plus-maze test at 7 days following drug administration. MAIN OUTCOME MEASURES： Blood β-endorphin and corticosterone levels were determined using enzyme-linked immunosorbent assay following treatment with ValerianajatamansiJones extract. Expressions of HPA axis-related genes were measured by cDNA microarray. RESULTS： Blood β-endorphin and corticosterone levels were significantly greater in the model group than in the normal group. Compared with the model group, levels decreased with Valeriana jatamansi Jones extract or estazolam treatment, particularly in the low-dose Valeriana jatamansi Jones group （P〈 0.01）. cDNA microarray results demonstrated that corticotropin-releasing hormone and Orexin, which are associated with HPA axis function, were differentially expressed; expression increased in the model group, but decreased in rats treated with Valerianajatamansi Jones extract. CONCLUSION： Valerianajatamansi Jones extract plays a role in regulating HPA axis function in a rat model of anxiety, and this effect was superior to estazolam.

Electroacupuncture (EA) Speeds Up the Regulation of Hypothalamic Pituitary Adrenal Axis Dysfunction in Acute Surgical Trauma Rats: Mediated by Hypothalamic Gamma-Aminobutyric Acid (GABA)_AReceptors

Hypothalamic Corticotropin-releasing factor (CRF) directly activates the hypothalamic pituitary adrenal axis (HPA axis) during the surgical trauma induced stress response. Electroacupuncture (EA) has been demonstrated to have stress relieving effects in breast surgery, colorectal surgery, prostatectomy and craniotomy. This study was aimed to investigate the hypothesis that EA could regulate hypothalamic CRF in surgical trauma rats. In experiment one, Sprague-Dawley (SD) male rats were divided into intact, model (10% partial hepatectomy), sham EA and EA group. Rats from the Sham EA and EA group were stimulated at ST36-Zusanli and SP6-Sanyiniiao acupoints twice, 24 hours before the surgery and immediately after the surgery. Expressions of hypothalamic CRF and CRFR, GABA receptors, glutamate decarboxylase (GAD), serum adrenocorticotropic hormone (ACTH) and Corticosterone (CORT) were observed at 2, 4, 8 and 24 h after the surgery by radioimmunoassay (RIA), western blot, real-time PCR and immunohistochemistry. In the experiment two, SD male rats were divided into the intact, model, model + vehicle, model + L-838,417 EA and EA + L838,417 group. It was found that hypothalamus CRF, serum ACTH and CORT levels were increased in model group compared with the intact group, and those in the EA group decreased in comparison with the model group. Compared with the model group, hypothalamus-aminobutyric acid (GABA) receptor Aα3 mRNA and protein expressions of the EA group raised strikingly. In conclusion, EA alleviated surgical stress response by improving the GABA synthesis in hypothalamus, thus enhancing GABA receptors’ inhibitory regulation of the HPA axis dysfunction in rats with acute surgical trauma.

The total flavonoids extracted from Xiaobuxin Tang reverse the hyperactivity of hypothalamic-pituitary-adrenal axis in chronically stressed rats

Objective To investigate the effect of XBXT-2 on the activity of hypothalamic-pituitary-adrenal(HPA)axis in chronic mild stress(CMS)model of rats.Methods Using ELISA to test the serum corticosterone,adrenocorticotropic hormone(ACTH)and corticotropin-releasing hormone(CRH)level in CMS rats;Using western blot to determine hippocampal glucocorticoids receptors(GR)expression in CMS rats.Results Co-administration of XBXT-2(25,50 mg·kg-1,p.o.,28 days,the effective doses for behavioral responses)significantly decreased the serum corticosterone and ACTH level in CMS rats,while the CRH level was not markedly affected by chronic stress or drugs.Moreover,XBXT-2 significantly increased the GR expression in the hippocampus of CMS rats.The same effects were observed in the positive control drug imipramine(10 mg·kg-1,p.o.).Conclusions The decrease of serum corticosterone and ACTH level,as well as the increase of hippocampal GR expression may be the mechanisms underlying the antidepressant action of XBXT-2,which may associate with HPA axis.

Individual Differences in Stress Responsiveness of the Hypothalamic-Pituitary-Adrenal Axis and Its Vasopressinergic Regulation in Old Monkeys

Stress adaptation is fundamental for health, and the hypothalamic-pituitary-adrenal axis (HPA) is one of its main mechanisms. Considerable data indicate that arginine vasopressin (AVP) related disturbances of stress adaptation can occur with aging. However, most studies of such kind have been performed on rodents, give contradictory results and fail to consider individual characteristics of the animals. The purpose of this study was to investigate individual HPA responsiveness to acute stress and its vasopressinergic regulation in old female rhesus monkeys that differ in their behavioral responses to stress. Animals with depression-like or anxiety-like behavior (DAB) responded with higher plasma levels of ACTH and AVP, lower levels of corticosteroids and higher cortisol/DHEAS molar ratios to restraint stress and to insulin-induced hypoglycemia compared with animals with healthy adaptive behavior. AVP and ACTH dynamics were closely correlated in most animals. AVP treatment produced differences in HPA responses similar to those produced by the stressors. The ACTH response to hypoglycemic stress in the DAB animal with highest HPA responsiveness was dramatically reduced by prior administration of a V1b receptor antagonist. These results suggest that the dysfunctions of HPA observed in old animals with DAB are caused by increased tone of the vasopressinergic system in regulation of HPA stress reactivity.

Relationship between glutamate in limbic system and hypothalamuspituitary-adrenal axis after middle cerebral artery occlusion in rats

Objective To study the features of the activity changes of glutamate (GLu ) in the hippocampusand hypothalamus and its effects on the activation of the hypothalamus-pituitary-adrenal axis (HPA ) duringacute cerebral ischemia (ACI ). Methods: The changes of Glu content, corticotrophin releasing hormone(CRH ) mRNA expression level and adrenocorticotropic hormone (ACTH ) concentration were determinedwith high-performance liquid chromatography (HPLC ) and in situ hybridization in different time intervals after middle cerebral artery occlusion (MCAO) in rats. Results: Glu content was increased rapidly in the hippocampus and hypothalamus 15 min after MCAO and reached the peak (the average Glu content in the hippocarnpus and hypothalamus were 21. 50± 2. 88 mg/g wt and 14. 20±2. 58 mg/g wt respectively) in the lsthour after MCAO and it returned rapidly to the base line level after reperfusion. The Gln content in the hippocampus and hypothalamus went up once more in the 24th hour of reperfusion, remained at a relatively highlevel till the 48th hour of reperfusion and then declined gradually. The expression level of CRH mRNA wasmarkedly enhanced in the temporal cortex, hippocampus and hypothalamus in the lst hour after MCAO andthis condition was kept on till the 96th hour of reperfusion. In the same time, the plasma level of ACTH wasrelatively increased. In the peak stage of reperfusion injury,there was a positive correlation of the Glu contentin the hypothalamus with the number of positive cells of CRH mRNA expression and the plasma level of ACTH. Conclusion: The central CRH system is possible to locate mainly in the limbic system and Gln might beone of the factors to induce excessive excitable stress response of the HPA axis.

Childhood stressful events, HPA axis and anxiety disorders

Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal(HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder(OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyperresponsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally,abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders.

Molecular mechanism of noradrenaline during the stress-induced major depressive disorder

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression.Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the brain.However,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant.Contrary to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant.In addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of MDD.Moreover,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC neurons.These inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD.In this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD.We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

Prolonged Adrenal Insufficiency after Unilateral Adrenalectomy for Cortisolic Adenoma

Background: The suppression of the hypothalamic-pituitary-adrenal axis by cortisol-secreting adrenocortical tumors is well recognized and requires peri- and postoperative hydrocortisone substitution. Case Presentation: A 48-year-old female patient with hypertension and progressive weight gain, the clinical signs of hypercorticism motivated a hormonal workup revealing an independent ACTH Cushing’s syndrome: with urinary free cortisol (UFC) at 649 nmol/24h (4× normal), adrenocorticotropin hormone (ACTH) at 1.5 ng/l. The rest of the hormonal workup was not performed due to a lack of financial means. An Adrenal CT scan showed a 4 cm right adrenal adenoma. The patient underwent a right adrenalectomy with an adrenal adenoma on pathological examination. The contralateral side was normal. The patient was treated with hydrocortisone 30 mg/d for 6 weeks then 15 mg/d, during the monitoring we noted a persistence of the adrenal insufficiency for now 4 years. Basal cortisol levels during follow-up were very low (<3 μg/dl) ruling out the need for synacthen stimulation tests. Conclusion: Adrenal cortisol tumors are recognized by suppression, the duration of hypothalamic-pituitary-adrenal axis suppression is variable from 11 to 60 months depending on the series, which depends on the duration, severity of hypercortisolism, tumor size and other unknown factors. A longer follow-up of these patients is necessary to look for recovery of the contralateral adrenal gland.

Improvement of Kidney Yang Syndrome by Icariin through Regulating Hypothalamus-Pituitary-Adrenal Axis

Objective： To investigate whether Epimedium brevicornu Maxim （EB） and icariin could exert their protective effects on hydrocortisone induced （HCI） rats by regulating the hypothalamus-pituitary-adrenal （HPA） axis and endocrine system and the possible mechanism. Methods： Male 10-week-old Sprague Dawley （SD） rats were allotted to 6 groups （A-F） with 12 each, group A was injected normal saline （NS） 3 mL/kg.day intraperitoneally, group A and B were given NS 6 mL/kg.day by gastrogavage, group B-F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/（kg·day） by gastrogavage, group E and F were given icariin 25 or 50 mg/（kg·day） by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone （CRH） and pituitary proopiomelanocortin （POMC） were detected by reverse transcription-polymerase chain reaction （RT-PCR）, and protein of pituitary POMC by Western-blot. Results： The serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B （P〈0.05）.The treatment with only icariin increased serum adrenocorticotropic hormone （ACTH） compared with group B （P〈0.05）. Conclusion： EB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC-derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex.

Relationship between glutamate in the limbic system and hypothalamus-pituitary-adrenal axis after middle cerebral artery occlusion in rats

Objective To investigate the features of glutamate activity in the limbic system and the effects of glutamate on the activation of the hypothalamus-pituitary-adrenal (HPA) axis throughout both acute cerebral ischemia and reperfusion. Methods The changes in glutamate content in the nervous cell gap,in corticotrophin releasing hormone (CHR) mRNA expression level in brain tissue,and in adrenocorticotropic hormone in blood plasma at different time-points after middle cerebral artery occlusion (MCAO) in rats were determined respectively with high-performance liquid chomatography (HPLC) and in situ hybridization.Results Glutamate content in the hippocampus and the hypothalamus increased rapidly at ischemia 15 minutes,and reached peak value (the averages were 21.05 mg/g±2.88 mg/g and 14.20 mg/g±2.58 mg/g,respectively) at 1 hour after middle cerebral artery occlusion. During recirculation,it returned rapidly to the baseline level. At 24 hours after reperfusion,it went up once more,and remained at a relative high level until 48 hours after reperfusion,and then declined gradually. CRH mRNA expression levels in the temporal cortex,hippocampus and hypothalamus were enhanced markedly at 1 hour ischemia and were maintained until 96 hours after reperfusion. At the same time,adrenocorticotropic hormone level in plasma was relatively increased. In the peak stage of reperfusion injury,there was a significantly positive correlation (n=15,r =0.566,P <0.05) of the glutamate contents in the hypothalamus with the number of cells positive for CRH mRNA expression level in the hypothalamus.Conclusion It is probable that the CRH system in the central nervous system is mainly distributed in the limbic system,and glutamate might be one of the trigger factors to induce excessive stress response in the HPA axis.

Inflammatory airway features and hypothalamic-pituitary- adrenal axis function in asthmatic rats combined with chronic obstructive pulmonary disease

Background Bronchial asthma （BA） and chronic obstructive pulmonary disease （COPD） are both inflammatory airway diseases with different characteristics. However, there are many patients who suffer from both BA and COPD. This study was to evaluate changes of inflammatory airway features and hypothalamic-pituitary-adrenal （HPA） axis function in asthmatic rats combined with COPD. Methods Brown Norway （BN） rats were used to model These three models were compared and evaluated with the inflammatory airway diseases of BA, COPD and COPD＋BA. respect to clinical symptoms, pulmonary histopathology, airway hyperresponsiveness （AHR）, inflammatory cytokines and HPA axis function. Results The inflammatory airway features and HPA axis function in rats in the COPD＋BA model group were greatly influenced. Rats in this model group showed features of the inflammatory diseases BA and COPD. The expression of inflammatory cytokines in this model group might be up or downregulated when both disease processes are present. The levels of corticotrophin releasing hormone mRNA and corticosterone in this model group were both significantly decreased than those in the control group （P 〈0.05）. Conclusions BN rat can be used as an animal model of COPD＋BA. By evaluating this animal model we found that the features of inflammation in rats in this model group seem to be exaggerated. The HPA axis functions in rats in this model group have been disturbed or impaired, which is prominent at the hypothalamic level.

Essence of"Shen(Kidney)Controlling Bones":Conceptual Analysis Based on Hypothalamic-Pituitary-Adrenal-Osteo-Related Cells Axis

As a traditional concept of Chinese medicine（CM）, the theory of ＂Shen（Kidney） controlling bones＂ has been gradually proven. And in modern allopathic medicine, the multiple mechanisms of bone growth, development and regeneration align with the theory. Shen deficiency as a pathological condition has a negative effect on the skeleton of body, specifically the disorder of bone homeostasis. Present studies indicate that Shen deficiency shares a common disorder characterized by dysfunction of hypothalamic-pituitary-adrenal（HPA） axis. HPA axis may be an important regulator of bone diseases with abnormal homeostasis. Therefore, we posit the existence of hypothalamic-pituitary-adrenal-osteo-related cells axis： cells that comprise bone tissue（osteo-related cells） are targets under the regulation of HPA axis in disorder of bone homeostasis. Chinese herbs for nourishing Shen have potential in the development of treatments for disorder of bone homeostasis.

The Ventral Ascending Noradrenergic Bundles Are Involved in the Stress Response to Immobilization in Rats

Stressful stimuli induced by immobilization are perceived as acute stress in rats. This acute stress activates corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), resulting in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. The ventral ascending noradrenergic bundles (V-NAB) from the brainstem innervate the PVN. To investigate the relationship between the response of the HPA axis and the V-NAB, we examined changes in plasma corticosterone, the final output of the HPA axis, and extracellular noradrenaline (NA) in the PVN following immobilization stress in rats that received bilateral 6-hydroxydopamine (6-OHDA) lesions of the V-NAB. 6-OHDA microinjection into the V-NAB reduced the magnitude of the responses of plasma corticosterone and extracellular NA in the PVN following immobilization stress. Our results suggest that V-NAB innervation of the PVN is involved in immobilization stress-induced activation of the HPA axis.

青少年非自杀性自伤患者自杀未遂与HPT轴和HPA轴功能改变的研究

目的探讨伴非自杀性自伤(non-suicidal self-injury,NSSI)行为的青少年心境障碍患者发生自杀未遂(suicide attempt,SA)与下丘脑-垂体-甲状腺(hypothalamic-pituitary-thyroid,HPT)轴功能和下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴功能改变的相关性。方法选取2020年12月至2022年5月在首都医科大学附属北京安定医院住院的近1年有NSSI史的13~19岁青少年心境障碍患者进行横断面调查,根据近一年是否存在SA将患者分为非SA组和SA组。根据SA发生的时间段(1个月)将SA组患者分为近期SA和既往SA。收集患者临床特征、甲状腺功能[游离三碘甲状腺原氨酸(free triiodothyronine,FT3)、游离甲状腺素(free thyroxine,FT4)、总三碘甲状腺原氨酸(total triiodothyronine,TT3)、总甲状腺素(total thyroxine,TT4)、促甲状腺激素(thyroid stimulating hormone,TSH)]及促肾上腺皮质激素(adrenocorticotropin,ACTH)、皮质醇(cortisol,CORT)水平。采用多因素Logistic回归分析SA的影响因素。结果共入组79例伴NSSI青少年心境障碍患者,其中49例(62.03%)发生SA,其中29例(59.18%)患者为近1个月内发生SA。单因素分析显示,SA组和非SA组患者在首次发病年龄、性别、教育水平方面差异有统计学意义(P<0.05)。近期SA组患者和既往SA组患者在年龄、TSH、ACTH水平存在差异(P<0.05)。Logistic回归分析显示,女性(P=0.027,OR=2.941,95%CI:1.131~7.649)是患者发生SA的独立危险因素,ACTH水平降低(P=0.043,OR=1.019,95%CI:1.001~1.037)是近期发生SA的相关因素。结论女性伴NSSI青少年心境障碍患者易发生SA,ACTH水平低是近期发生SA的危险因素。

慢性应激导致卵巢早衰的中西医机制探讨

随着生物-心理-社会医学模式的不断深化,慢性应激已成为威胁机体身心健康的重要因素。卵巢早衰是妇科常见疑难内分泌疾病,发病率呈逐年增长趋势,且患病群体日益年轻化。慢性应激是导致卵巢早衰的重要原因之一。慢性应激可导致下丘脑-垂体-肾上腺轴功能持续亢进,引发机体神经内分泌代谢紊乱,抑制下丘脑-垂体-卵巢轴的正常功能,进而发展为卵巢早衰。中医情志致病理论与现代应激理论一致,中医的“肝”是机体调节心理应激反应的核心,“肾”是调节卵巢发挥正常功能的根本保障。肾虚肝郁是导致卵巢早衰的根本病因。因此,身心同治、调畅情志将成为临床治疗卵巢早衰的新趋势。

基于下丘脑-垂体-肾上腺轴探讨电针对功能性消化不良大鼠的作用机制

目的探讨电针印堂、内关、足三里对FD大鼠下丘脑-垂体-肾上腺轴的可能作用机制。方法40只SD大鼠随机分为空白组、模型组和电针组。采用夹尾、不规律饮食以及冰生理盐水灌胃法复制FD模型。造模后,电针组行针刺干预,每天1次,每次30 min,连续14天。记录大鼠的一般状态;旷场实验检测大鼠的自主行为及紧张度;HE染色法观察大鼠胃黏膜形态及炎症反应;实时荧光定量PCR法检测大鼠下丘脑5-羟色胺3受体(5-HT3R)、促肾上腺皮质激素释放激素(CRH)的表达;蛋白免疫印迹法检测大鼠十二指肠促肾上腺皮质激素释放激素受体2(CRHR2)、NOD样受体蛋白6(NLRP6)蛋白表达;阿利新蓝染色观察大鼠十二指肠黏膜上皮形态及杯状细胞的阳性表达。结果与空白组相比,模型组大鼠一般状态、旷场自主运动距离、运动速度、十二指肠CRHR2、NLRP6蛋白均大幅下降(P<0.05),下丘脑5-HT3R、CRH mRNA明显升高(P<0.05)。与模型组相比,电针组大鼠一般状态、旷场自主运动距离、运动速度、十二指肠CRHR2、NLRP6蛋白及杯状细胞的表达均明显提高(P<0.05),下丘脑5-HT3R、CRH mRNA大幅下降(P<0.05)。模型组大鼠胃黏膜可见疏松的结缔组织,黏膜下层轻度水肿,淋巴细胞增生;空白组和电针组大鼠胃黏膜结缔组织排列紧密,胃腺间质无明显增生,未见炎症细胞。结论电针印堂、内关、足三里可能是通过提升十二指肠CRHR2、NLRP6蛋白和杯状细胞表达,抑制下丘脑5-HT3R、CRH的表达,来提高FD大鼠自主运动水平,缓解焦虑,修复缺损的肠道黏膜屏障,恢复下丘脑-垂体-肾上腺轴的正常功能。

诱导抑郁症患者小胶质细胞炎性反应的机制

小胶质细胞炎性反应是抑郁症患者及相关动物模型中广泛观察到的病理现象,与抑郁症密切相关。抑郁症中诱导小胶质细胞炎性反应的机制包括下丘脑-垂体-肾上腺(HPA)轴激活后糖皮质激素水平变化直接或间接的调控作用、肠道微生物代谢物通过脑肠轴中免疫与神经途径的作用以及损伤相关分子模式(DAMPs)对小胶质细胞的直接激活作用等。

下丘脑-垂体-肾上腺轴和性腺轴在围绝经期抑郁症中的作用(综述)

抑郁症作为常见的情感类精神障碍疾病,已成为世界范围内第二大健康负担。抑郁症表现出的一个重要特点是女性患抑郁症的可能性是男性的两倍以上,这可能与女性神经内分泌激素水平的变化有关,比如围产期抑郁、围绝经期抑郁(perimenopausal depression,PMD)。围绝经期是女性生殖的脆弱窗口,受各方面因素的影响,尤其是体内激素水平的波动使下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴和下丘脑-垂体-性腺(hypothalamus-pituitary-gonadal,HPG)轴功能发生紊乱,导致机体出现情绪低落和焦虑不安等抑郁症状。本文综述近年来HPA轴和HPG轴相互作用导致围绝经期抑郁症的研究进展,以期为围绝经期抑郁症以及抑郁症的诊断与治疗提供新的思路及参考。

孤啡肽改善尼古丁戒断大鼠的焦虑样行为及其对HPA轴与炎症因子的调控机制

目的:探讨孤啡肽(nociceptin/orphanin FQ,N/OFQ)对尼古丁(nicotine,NIC)戒断大鼠焦虑样行为的改善作用及其对下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴神经递质与炎症因子表达的调控机制。方法:成年雄性Sprague-Dawley大鼠32只,随机分为正常对照组、NIC戒断模型组、N/OFQ低剂量治疗组和N/OFQ高剂量治疗组,每组各8只。模型组和N/OFQ治疗组大鼠每次皮下注射NIC(0.4 mg/kg),每天2次,连续7 d,然后戒断3 d制备大鼠尼古丁戒断焦虑模型。戒断期间N/OFQ低、高剂量治疗组大鼠每天一次侧脑室注射N/OFQ 1nmol和N/OFQ 10 nmol,连续3 d。第3次给药10 min后,利用旷场实验(open filed,OF)和高架十字迷宫实验(elevated plus maze,EPM)检测大鼠行为学变化;ELISA检测血清中促肾上腺皮质激素释放激素(corticotrophin-releasing hormone,CRH)、促肾上腺皮质激素(adrenocor ticotropic hormore,ACTH)和皮质酮(coritosterone,CORT)浓度以及血清中炎症因子肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白细胞介素1β(interleukin-1β,IL-1β)和IL-6的浓度;用RT-qPCR检测大脑杏仁核中央核(centraln nucleus of amygdala,CeA)中TNF-α、IL-1β和IL-6的mRNA表达水平;HE染色光镜下观察海马组织CA1区神经元形态学变化;利用高效液相色谱检测大脑CeA的去甲肾上腺素(norepinephrine,NE)水平;利用Western blot检测大脑CeA的酪氨酸羟化酶(tyrosine hydroxylase,TH)蛋白表达。结果:与模型组比较,N/OFQ低、高剂量治疗组大鼠在OF中央区活动距离和活动时间显著升高(P<0.05或P<0.01),EPM的开放臂进入次数和停留时间百分率显著升高(P<0.05或P<0.01);同时,N/OFQ低、高剂量治疗组显著抑制NIC戒断大鼠血清中CRH、ACTH和CORT浓度(P<0.01);显著抑制血清中TNF-α、IL-1β和IL-6等炎症因子水平以及大脑CeA中TNF-α、IL-1β和IL-6 mRNA表达水平(P<0.05或P<0.01);N/OFQ低、高剂量治疗组显著减轻大鼠海马CA1区神经元损伤;并且显著降低NIC戒断大鼠大脑CeA中NE的水平和TH蛋白的表达(P<0.01)。结论:N/OFQ改善NIC戒断大鼠焦虑样行为,其机制通过HPA轴神经递质与炎症因子的调控所介导。

醒脑解郁方灌胃对大鼠卒中后抑郁的治疗作用及机制

目的 观察醒脑解郁方对大鼠卒中后抑郁(PSD)的治疗作用,并探讨其作用机制与下丘脑—垂体—肾上腺(HPA)轴的关系。方法 取雄性SD大鼠60只,随机分为正常对照组、PSD组、氟西汀组、醒脑解郁方低剂量组、醒脑解郁方高剂量组,每组各12只。正常对照组正常饲养不做干预,其余4组采用大脑中动脉栓塞联合慢性不可预知温和刺激(CUMS)制备PSD模型。CUMS期间氟西汀组给予氟西汀溶液0.2 mg/100 g灌胃,醒脑解郁方低剂量组和高剂量组分别给予1.05、2.10 g/mL醒脑解郁方灌胃,正常对照组、PSD组给予1 mL/100 g生理盐水灌胃。根据大鼠体质量、强迫游泳实验、糖水消耗实验和旷场实验评估抑郁状态;处死大鼠,取脑组织,采用HE染色法观察海马组织病理形态;采用ELISA法检测血清HPA轴相关激素促肾上腺皮质激素(ACTH)、皮质醇(CORT);Western blotting法检测HPA轴相关激素海马糖皮质激素受体(GR)、下丘脑促肾上腺皮质激素释放激素(CRH)蛋白。结果 与正常对照组比较,PSD组体质量降低、强迫游泳测试时间缩短、糖水消耗量减少、水平及垂直运动得分降低,海马组织神经元数量缺失明显,呈现炎性改变,血清ACTH、CORT水平升高,海马组织GR蛋白表达水平降低,下丘脑组织CRH蛋白表达水平升高(P均<0.01)。与PSD组比较,氟西汀组和醒脑解郁方低、高剂量组体质量增加、强迫游泳时间延长、糖水消耗量增多、水平及垂直运动得分增加,海马组织神经元受损程度较轻,水肿现象减少,细胞存活率提高,细胞排列紧密;血清ACTH、CORT水平降低,海马组织GR蛋白表达水平升高,下丘脑组织CRH蛋白表达水平降低(P均<0.01)。结论 醒脑解郁方能够改善PSD大鼠的抑郁样行为,其机制可能是通过抑制HPA轴过度激活从而减轻海马神经元损伤发挥作用。