丙戊酸钠抗抑郁作用涉及改善氧化应激平衡和提升脑源性神经营养因子表达

目的:探讨丙戊酸钠减轻慢性不可预见刺激(CUS)致大鼠抑郁行为是否与改善机体氧化应激功能及脑源性神经营养因子(BDNF)表达有关.方法:雄性SD大鼠60只,随机分为对照组(CG),模型组(MG),丙戊酸钠灌胃正常组(VAPC)和丙戊酸钠灌胃模型组(VAPM).以开场试验和强迫游泳试验评价大鼠焦虑抑郁行为;采用常规生物化学方法测定大脑皮质丙二醛(MDA)含量及超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活力;荧光定量PCR和Western blot检测海马脑源性神经营养因子(BDNF) mRNA和蛋白表达.结果:与CG组相比,MG组大鼠开场试验水平得分和垂直得分明显降低,强迫游泳试验不动时间显著延长,MDA含量升高,SOD及CAT活力明显下降,海马BDNF mRNA和蛋白表达均明显降低.给予丙戊酸钠可明显阻遏上述变化,但对正常大鼠无明显影响.结论:CUS致大鼠焦虑抑郁行为与体内氧化及抗氧化失衡,海马BDNF表达减少有关;丙戊酸钠能阻遏这种变化,从而显示减轻CUS所致大鼠焦虑抑郁行为作用.     

脑源性神经营养因子在抑郁症中的研究进展

脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是参与机体情绪和认知功能至关重要的调节因子,能够促进脑内神经发生和突触发育。在抑郁患者及抑郁动物模型中,BDNF前体（brain-derived neurotrophic factor precursor,proBDNF）和前肽水平升高,BDNF成熟体（mature brain-derived neurotrophic factor,mBDNF）水平降低;抗抑郁药物治疗后,能够抑制proBDNF以及BDNF前肽的表达,促进mBDNF/proBDNF蛋白比值的升高。目前临床常见抗抑郁药的抗抑郁作用多依赖于BDNF及相关蛋白的信号转导。本文通过查阅文献,对BDNF及其相关因子在抑郁症中的作用进行总结。     

吗啡依赖大鼠海马内脑源性神经营养因子的表达

目的研究脑源性神经营养因子（BDNF）在大鼠吗啡精神依赖中所起的作用。方法大鼠连续6d腹腔注射吗啡10mg／kg,诱导吗啡条件性位置偏爱（CPP）形成。免疫组化法测定大鼠海马内BDNF的表达。结果经6d吗啡训练后,吗啡组在伴药侧的停留时间较对照组显著增加（P〈O．01）。吗啡组大鼠海马内BDNF的阳性细胞数、平均光密度值分剐为（99．18±15．85）、（188．29±22．42）,均显著高于对照组（36．01±9．53）、（73.28±13．36）（P〈0．01,P〈O．01）。结论BDNF在慢性吗啡处理大鼠海马内的表达上调,证实BDNF参与了慢性吗啡依赖生物学过程,推测BDNF可能在精神依赖中起重要作用。     

氟西汀对大鼠海马脑源性神经营养因子基因表达的作用

目的　为了进一步探讨抗抑郁药作用的分子机制。方法　采用原位杂交技术 (地高辛标记的BDNFcDNA探针 )检测长期给予抗抑郁药氟西汀及生理盐水大鼠海马神经元BDNFmRNA的表达。结果　与生理盐水组相比 ,氟西汀组表达增强 ,尤以CA3、CA1区为甚。结论　长期给药后脑内有关区域BDNF表达改变可能是抗抑郁效应发生的受体后分子作用机制之一     

脑源性神经营养因子与中枢神经损伤

<正>脑源性神经营养因子(Brain-derived neurotrophie factor,BDNF)由Barde等于1982年首次从猪脑提取液中获得,是相对分子质量为1213kD的碱性蛋白,为神经营养素家族成员之一,广泛分布于中枢神经系统(Central nervous system,CNS)。目前国内外已经对BDNF的生物学作用进行了广泛的研究,证实它不仅在中枢神经系统发育过程中对神经元的生存、分化、生长和维持神经元正常的生理功能起     

脑源性神经营养因子的研究进展

近年来,科学研究发现神经营养因子是参与调控神经系统多种生理功能的一种蛋白质。其中,脑源性神经营养因子是一种在脑内合成的小分子二聚体蛋白质,对中枢系统神经元的生长、发育、分化、再生和修复具有重要作用。本文对脑源性神经营养因子的结构、功能、疾病相关性及临床应用前景进行了综述。     

BCEF0083对慢性应激抑郁模型大鼠海马神经元及脑源性神经营养因子mRNA表达的影响研究

目的:研究BCEF0083对慢性应激抑郁模型大鼠海马神经元及脑源性神经营养因子(BDNF)mRNA表达的影响。方法:将大鼠随机分为对照组、模型组、吗氯贝胺20mg/kg组以及BCEF0083100、50、25mg/kg组,用HE染色法观察海马神经元数目的变化,用逆转录-聚合酶链反应法检测海马BDNFmRNA的表达。结果:BCEF0083可增加慢性应激抑郁模型大鼠海马神经元数目及上调BDNFmRNA的表达。结论:BCEF0083的抗抑郁作用可能与增加慢性应激抑郁模型大鼠海马神经元数目及上调BDNFmRNA的表达有关。     

产后抑郁症患者血清脑源性神经营养因子含量及与临床相关性分析

目的 探讨产后抑郁患者血清脑源性神经营养因子(BDNF)含量及与临床相关性分析.方法 采用ELISA测定48例产后抑郁患者及30例健康产妇血浆中BDNF的含量,然后比较两组间差别及产后抑郁组中BDNF含量与爱丁堡产后抑郁评分之间的关系.结果 产后抑郁组患者EPDS评分、血清BDNF含量均高于对照组,其差异具有统计学意义(P<0.01);Pearson相关分表明,产后抑郁患者与对照组患者EPDS评分和血清BDNF含量之间呈正相关(r=0.741,P=0.000).结论 BDNF与抑郁病情相关,临床中可以作为预测产后抑郁早期发生及临床疗效评定生物指标.     

血清脑源性神经营养因子对帕罗西汀治疗惊恐障碍效果的影响

目的:探讨脑源性神经营养因子(BDNF)在帕罗西汀治疗惊恐障碍中的可能作用。方法:接受帕罗西汀治疗12周的惊恐障碍患者45例(治疗组),按治疗前后汉密尔顿焦虑量表(HAMA)减分率分为有效组(≥50%,29例)和无效组(<50%,16例)。采用惊恐相关症状量表(PASS)、17项汉密尔顿抑郁量表(HAMD)、HAMA、临床总体印象量表(CGI)评定疾病严重程度和改善程度;采用酶联免疫吸附法测定其血清BDNF浓度,并与30名正常对照者(对照组)比较;对治疗组的血清BDNF浓度与各相关因素进行Spearman相关分析。结果:有效组BDNF水平高于无效组和正常对照组(P<0.05),无效组的BDNF水平则低于正常对照组(P<0.05);治疗组血清BDNF水平治疗后的PASS分值(r=-0.540,P=0.000)和HAMA分值(r=-0.491,P=0.001)呈负相关,与治疗前后HAMA评分差值(r=0.425,P=0.004)和PASS评分差值(r=0.522,P=0.000)呈正相关。结论:外周循环中BDNF水平减少在惊恐障碍的病理生理机制中起着重要的作用,可能是帕罗西汀疗效的预测因素。     

17β-雌二醇对卵巢切除小鼠海马内脑源性神经营养因子及神经营养因子 3表达的影响(英文)

目的　为确定雌激素可能具有的神经营养调节作用。方法　采用蛋白质印迹法检测上述指标的变化。结果　与卵巢未切除对照组相比 ,小鼠卵巢切除 10周后海马内脑源性神经营养因子 (BDNF)表达水平明显下降 ,给予 17β 雌二醇 (2 .4或 4 .8μg·d- 1,sc ,连续 12周 )替代具有明显的改善作用 (P <0 .0 1)。但卵巢切除及 17β 雌二醇替代对海马内神经营养因子 3表达水平无明显影响。结论　海马内BDNF表达水平的改变与雌激素缺乏具有密切关系。雌激素对调节海马内BDNF水平具有重要作用。     

改善氧化/抗氧化应激平衡及NET和5-HTT表达与瑞波西汀抗抑郁作用有关

目的探讨瑞波西汀抗慢性轻度不可预见性刺激(CUMS)致大鼠抑郁症行为与机体氧化/抗氧化应激平衡以及去甲肾上腺素转运体(NET)和5-羟色胺转运体(5-HTT)表达的关系。方法♂SD大鼠60只,随机分为正常对照组(NG)、模型组(MG)、瑞波西汀(0.7 mg.kg-1.d-1)灌胃的模型组(RMG)和正常对照组(RNG)。采用孤养结合CUMS方式建立大鼠抑郁模型。以开场实验与糖水消耗实验评价大鼠抑郁行为,生物化学方法检测大鼠血清丙二醛(MDA)含量及超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活力,RT-PCR法测定脑桥NET和海马5-HTT mRNA表达;光镜观察HE染色海马切片的病理形态改变。结果与NG组相比,MG组大鼠在开场实验中水平得分、垂直得分和理毛次数以及糖水消耗均明显降低,血清MDA含量升高,SOD和CAT活力及NET和5-HTT表达均下降,海马神经细胞出现明显核固缩和染色加深;给予瑞波西汀明显阻遏CUMS诱导的上述变化,但对正常组大鼠无影响。结论瑞波西汀可能通过逆转氧化/抗氧化应激系统失衡,增加NET和5-HTT的表达而产生抗抑郁作用。     

Maternal separation attenuates the effect of adolescent social isolation on HPA axis responsiveness in adult rats

Adverse early life experiences that occur during childhood and adolescence can have negative impacts on behavior later in life. The main goal of our work was to assess how the association between stressful experiences during neonatal and adolescent periods may influence stress responsiveness and brain plasticity in adult rats. Stressful experiences included maternal separation and social isolation at weaning. Three hours of separation from the pups (3–14 PND) significantly increased frequencies of maternal arched-back nursing and licking-grooming across the first two weeks postpartum. Separation also induced a long-lasting increase in dams blood levels of corticosterone. Maternal separation did not modify brain and plasma allopregnanolone and corticosterone levels in adult offspring, but they demonstrate partial recovery from the reduction induced by social isolation during adolescence. Moreover, the enhancement of corticosterone and allopregnanolone levels induced by foot shock stress in socially isolated animals that were subjected to maternal separation was markedly reduced with respect to that observed in animals that were just socially isolated. All experimental groups showed a significant reduction of BDNF and Arc protein expression in the hippocampus. However, the reduction of BDNF observed in animals that were maternally separated and subjected to social isolation was less significantly pronounced than in animals that were just socially isolated. The results sustained the mismatch hypothesis stating that aversive experiences early in life trigger adaptive processes, thereby rendering an individual to be better adapted to aversive challenges later in life.     

Antidepressant and anxiolytic effects of the proprietary Chinese medicine Shexiang Baoxin pill in mice with chronic unpredictable mild stress

Depression and anxiety often co-occur with cardiac diseases. The Shexiang Baoxin pill (SBP) is a proprietary Chinese medicine initially used to treat cardiac conditions. This study explored whether SBP has antidepressant and anxiolytic effects in addition to hormonal and psychotropic mechanisms. Mice underwent 6 weeks of chronic unpredictable mild stress (CUMS) to induce depression- and anxiety-like behavior. During the 6-week experiment, mice received SBP at intragastric doses of 20.25 mg/kg or 40.5 mg/kg daily. Animals were then tested for depression in sucrose preference, forced-swimming, and tail suspension paradigms, and for anxiety in open field and elevated plus maze tests. Both SBP doses significantly reduced anhedonic behavior in the sucrose preference test; the high SBP dose also increased the number of entries into the central zone of the open field. SBP-treated mice had markedly lower blood levels of corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) than stressed mice treated with vehicle. Either low- or high-dose SBP reversed stress-induced reductions of norepinephrine (NE) and dopamine (DA) metabolites and the expression levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) in related brain regions. These results suggest that SBP could prevent and alleviate prolonged stress-induced anhedonia and anxiety in association with its suppression of the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, modulation of brain monoamine neurotransmitter metabolism and neurotrophins. SBP may be particularly suitable for the management of depressive and anxiety disorders in patients with cardiac conditions.     

Influence of chronic stress on brain corticosteroid receptors and HPA axis activity

BackgroundDisruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study, the dynamics of the changes in GRs, in brain structures involved in stress reactions, prefrontal cortex, hippocampus and hypothalamus was compared with the peripheral hypothalamo-pituitary-adrenocortical (HPA) axis hormones response to chronic stress.MethodsRats were exposed to 10 min restraint or restrained twice a day for 3, 7 or 14 days, and 24 h after the last stress session exposed to homotypic stress for 10 min. Control rats were not restrained. After rapid decapitation at 0, 1, 2, and 3 h after stress termination, trunk blood for plasma adrenocorticotropic hormone (ACTH) and corticosterone determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Plasma hormones were determined using commercially available kits and glucocorticoids and mineralocorticoids protein levels in brain structure samples were determined by western blot procedure.ResultsRestraint stress alone significantly decreased glucocorticoid receptor (GR) level in prefrontal cortex and hippocampus, and increased mineralocorticoid receptor (MR) level in hypothalamus. Prior repeated stress for 3 days significantly increased GR protein level in hippocampus and diminished that level in hypothalamus in 7 days stressed rats. Acute stress-induced strong increase in plasma ACTH and corticosterone levels decreased to control level after 1 or 2 h, respectively. Prior repeated stress for 3 days markedly diminished the fall in plasma ACTH level and repeated stress for 7 days moderately deepened this decrease. Plasma ACTH level induced by homotypic stress in rats exposed to restraint for 3, 7, and 14 days did not markedly differ from its control level, whereas plasma corticosterone response was significantly diminished. The fast decrease of stress-induced high plasma ACTH and corticosterone levels was accompanied by a parallel decline of GR level only in prefrontal cortex but not in the hippocampus or hypothalamus.ConclusionsComparison of the dynamics of changes in plasma ACTH and corticosterone level with respective alterations in GR and MR in brain structures suggests that the buffering effect of repeated stress depends on the period of habituation to stress and the brain structure involved in regulation of these stress response.     

右美托咪定对体外循环后围术期神经认知障碍老龄大鼠海马HPA轴和BDNF-ERK-CREB信号通路的影响

目的 评价右美托咪定对体外循环后围术期神经认知障碍老龄大鼠HPA轴和海马BDNF-ERK-CREB信号通路的影响.方法 选择老龄健康雄性Sprangue Dwaley大鼠120只,18～20月龄,体重400～550 g.采用随机数字表法将其分为4组(n=30):对照组(C组)、体外循环组(T组)、体外循环+右美托咪定组...     

高脂饲料加STZ联合诱导的大鼠糖尿病模型HPA轴功能变化与糖脂代谢的关系

目的研究高脂饲料加小剂量STZ联合诱导的糖尿病大鼠HPA轴功能变化与糖脂代谢的关系。方法采用长期高脂饲料加STZ(30mg·kg-1ip)联合诱导的糖尿病模型,将其分为4组,即正常对照组、模型组、地黄寡糖(ROS)组和二甲双胍组,ROS组灌胃地黄寡糖(200mg·kg-1.d-1),二甲双胍组灌胃盐酸二甲双胍(200mg·kg-1.d-1);每周测定1次大鼠血糖和体重,给药4wk后收集24h尿液并断头处死,测定血浆中血脂(TC、TG、HDL-C)、胰岛素、CRH、ACTH、皮质酮及下丘脑中CRH、垂体中ACTH、24h尿液中尿糖及皮质酮(CORT)含量。结果与正常对照组相比,模型组血糖、尿糖、TC、TG均明显升高,肝糖原、HDL-C含量下降,地黄寡糖能逆转这些改变。同时模型与正常对照组相比,胰岛素和下丘脑中CRH下降明显,血浆中ACTH、CORT及垂体中ACTH、24h尿液中CORT总量都有所升高,ROS对其有一定的改善作用。结论高脂饲料加STZ诱导的糖尿病模型糖脂代谢紊乱可能与HPA的活性升高有关,中药地黄寡糖的降血糖作用可能与改善HPA功能有一定关系。     

Interactions of chronic lead exposure and intermittent stress: consequences for brain catecholamine systems and associated behaviors and HPA axis function.

Elevated lead (Pb) burden and high stress levels are co-occurring risk factors in low socioeconomic status (SES) children. Our previous work demonstrated that maternal Pb exposure can permanently alter hypothalamic-pituitary-adrenal (HPA) axis function and responsivity to stress challenges in offspring. The current study sought to determine the consequences of chronic Pb exposures initiated later in development combined with variable intermittent stress challenges. Male rats were exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate drinking solutions (producing blood Pb levels of <5, 9-15, and 23-27 mug/dl, respectively). Pb itself decreased basal plasma corticosterone, with greater effects at 50 than 150 ppm; 150 ppm reduced both cytosolic and nuclear glucocorticoid receptor binding. Responsivity to stress challenges including novelty, cold, and restraint, was measured as changes in Fixed Interval (FI) schedule-controlled behavior in a subset of rats within each group. FI performance was modified by novelty stress only in Pb-treated rats, whereas cold and restraint stress effects were comparable across groups. Novelty elevated corticosterone equivalently across groups, but cold stress markedly increased corticosterone only in Pb-treated groups. The pattern of Pb-induced changes in serotonin (5-HT) or its metabolite 5-HIAA in frontal cortex, nucleus accumbens, striatum, and hypothalamus resembled that observed for basal corticosterone levels indicating a relationship between these variables. In addition to suggesting the potential for HPA axis-mediated effects of Pb on the central nervous system, these findings also raise questions about whether single chemicals studied in isolation from other relevant risk factors can adequately identify neurotoxic hazards.     

HPA axis response to psychological stress and treatment retention in residential substance abuse treatment: A prospective study

Introduction

Substance abuse treatment programs are often characterized by high rates of premature treatment dropout, which increases the likelihood of relapse to drug use. Negative reinforcement models of addiction emphasize an individual's inability to tolerate stress as a key factor for understanding poor substance use treatment outcomes, and evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to an individual's inability to respond adaptively to stress. The aim of the current study was to examine whether HPA axis response to stress is predictive of treatment retention among a sample of drug users in residential substance abuse treatment.

Method

Prospective study assessing treatment retention among 102 individuals enrolled in residential substance abuse treatment. Participants completed two computerized stress tasks, and HPA axis response to stress was measured via salivary cortisol at five time points from baseline (pre-stress) to 30 min post-stress exposure.

Results

The main outcome measures were treatment dropout (categorical) and total number of days in treatment (continuous). A significantly higher salivary cortisol response to stress was observed in treatment dropouts compared to treatment completers. Further, Cox proportional hazards survival analyses indicated that a higher peak cortisol response to stress was associated with a shorter number of days to treatment dropout.

Conclusions

Results indicate that a higher salivary cortisol level in response to stress is associated with an inability to remain in substance abuse treatment. These findings are the first to document a biological marker of stress as a predictor of substance abuse treatment dropout, and support the development and implementation of treatments targeting this vulnerability.     

Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice

Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One half of the animals in each group were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.