Brain‐derived Neurotrophic Factor Signaling Mediates the Antidepressant‐like Effect of the Total Flavonoids of Alpiniae Oxyphyllae Fructus in Chronic Unpredictable Mild Stress Mice

The present study verified the antidepressant‐like effects of the total flavonoids of Alpinia oxyphylla Miq. (AOF) using the chronic unpredictable mild stresses paradigm and explored the mechanism that underlies antidepressant‐like effects of AOF in mice. Previous research has shown that tropomyosin‐related kinase B (TrkB) receptor‐mediated extracellular regulated protein kinases (ERK) signaling pathways participate in depression pathophysiology. Therefore, we aimed to explore whether AOF improved depression‐like behaviors by increasing activity of ERK pathways mediated by TrkB. Results showed that AOF significantly reduced the immobility time in the forced swimming test and increased the sucrose preference in sucrose preference test. In addition, decreased phosphorylated cyclic adenosine monophosphate response element‐binding protein (pCREB)/CREB, pERK/ERK, and pTrkB/TrkB levels in the hippocampus induced by chronic unpredictable mild stresses were reversed by intragastric administration of AOF. Results suggested that AOF increased pCREB/CREB, pERK/ERK, and pTrkB/TrkB levels by acting on the TrkB receptor. To verify this hypothesis, mice were pretreated with the TrkB inhibitor K252a (or 0.1% dimethyl sulfoxide, intraperitoneally, 2 weeks), before the intragastric administration of AOF. This resulted in an absence of antidepressant‐like effects, as well as no activation of pERK/pCREB/BDNF signaling pathways. Results demonstrated that AOF might exert antidepressant‐like effects by targeting TrkB receptor‐mediated pERK/pCREB/BDNF signal systems, which could help to identify the AOF receptor. Copyright © 2016 John Wiley & Sons, Ltd.     

Schisandrae Chinensis Fructus inhibits behavioral deficits induced by sleep deprivation and chronic unpredictable mild stress via increased signaling of brain‐derived neurotrophic factor

The present study was undertaken to explore the interactions between sleep deprivation (SD) and Schisandrae Chinensis Fructus (SCF) treatment in the antidepressant‐like effects. We observed that SD aggravated the anxiety‐like behavior induced by chronic unpredictable mild stress (CUMS) in the elevated plus maze test. However, the forced swimming test and sucrose preference test showed that SD (12 hr) alleviated the depressive symptoms and SD (72 hr) has the opposite effects. Administration of SCF showed a promising therapeutic effect on depression and anxiety induced by CUMS and SD. Moreover, SCF could potential strengthen the antidepressant‐like effects of SD (12 hr) according to the behavioral tests. In addition, the BDNF level in hippocampus was elevated by SD (12 hr) and SCF treatment and together with the upregulation of TrkB/CREB/ERK and PI3K/AKT/GSK3β/mTOR signaling pathways. Besides, the protein levels of p70S6K and PSD95, which are downstream targets of mTOR, also increased by the treatment. These results indicated that the antidepressant‐like effect of SCF in the CUMS depends on the activation of BDNF and the modulation of TrkB/CREB/ERK and PI3K/AKT/GSK3β/mTOR signaling cascades, and SD (12 hr) shared a common etiology consisting of complex bidirectional interactions with SCF.     

逍遥散抗抑郁作用的BDNF/CREB信号机制

目的:探讨逍遥散抗抑郁作用的BDNF/CREB信号机制。方法:采用小鼠慢性温和不可预知应激(CUMS)结合孤养抑郁模型,逍遥散水煎液30g/kg灌胃给药4周,测定小鼠体重、自主活动及糖水消耗量的变化以评价药物的抗抑郁效应。ELISA法测定血清BDNF水平,实时荧光定量聚合酶链式反应(real-time PCR)测定小鼠海马及皮质部位CREB、BDNF mRNA表达,Western-blot方法测定小鼠脑内ERK1/2及磷酸化ERK1/2(pERK1/2)的蛋白表达量。结果:与模型组比较,逍遥散30g/kg能提高模型小鼠体重、自主活动及糖水消耗量,并有提高模型动物血清BDNF含量的趋势;逍遥散30g/kg显著增加模型小鼠海马BDNF、CREB mR-NA及皮质BDNF mRNA的表达量,对模型动物海马部位pERK1/2的表达量有提高趋势。结论:逍遥散对CUMS结合孤养的小鼠抑郁模型具有抗抑郁效应,作用机制与干预BDNF/CREB信号途径的关键分子的表达与功能有关。     

Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling

Chronic traumatic stress results in various psychiatric disorders, especially posttraumatic stress disorder (PTSD). Previous study demonstrated that curculigoside (CUR) a component of Rhizoma Curculiginis prevented fear extinction and stress-induced depression-like behaviors. However, its effects on PTSD and the mechanisms are still not completely clear. In this study, we observed typical PTSD-like phenotypes, synaptic deficit, and reduction of BDNF/TrkB signaling pathway in mice receiving modified single prolonged stress and electrical stimulation (SPS&S). By contrast, systemic administration of CUR blocked PTSD-like phenotypes and synaptic deficits, including reduction of BDNF/TrkB signaling pathway, GluA1 and Arc expression. Importantly, CUR reversed the impairment of PKA signaling pathway elicited by PTSD. We further confirmed that the effects of CUR on synaptic function were through PKA signaling pathway, as H-89, an inhibitor of PKA blocked the effect of CUR on behavioral changes and BDNF/TrkB signaling pathway. Thereafter, we verified that CUR on synaptic function were through PKA pathway using direct intracerebral injection of CUR and H-89. Direct intracerebral injection of CUR activated PKA/CREB/BDNF/TrkB, which was blocked by H-89. Additionally, the docking results showed high binding energies of CUR with A2AR, AC, PRKACA, and PRKAR1A, which might indicate that CUR functions through regulating PKA signaling pathway. In conclusion, CUR prevented the behavioral changes and hippocampal synaptic deficits elicited by PTSD through activating cAMP-PKA signaling.     

Antidepressant‐like effects of 20(S)‐protopanaxadiol in a mouse model of chronic social defeat stress and the related mechanisms

20(S)‐Protopanaxadiol (PPD) is a basic aglycone of the dammarane triterpenoid saponins and exerts antidepressant‐like effects on behaviour in the forced swimming test (FST) and tail suspension test (TST) and in rat olfactory bulbectomy depression models. However, the antidepressant effects of PPD have not been studied thoroughly. The objective of the present study was first to investigate the effect of PPD on depression behaviours induced by chronic social defeat stress (CSDS) in mice. The results showed that CSDS was effective in producing depression‐like behaviours in mice, as indicated by decreased responses in the social interaction test, sucrose preference test, TST, and FST, and that this effect was accompanied by noticeable alterations in the levels of oxidative markers (superoxide dismutase, catalase, and lipid peroxidation) and monoamines (5‐HT and NE) in the hippocampus and serum corticosterone levels. Additionally, western blot analysis revealed that CSDS exposure significantly downregulated BDNF, p‐TrkB/TrkB, p‐Akt/Akt, and p‐mTOR/mTOR protein expression in the hippocampus. Remarkably, chronic PPD treatment significantly ameliorated these behavioral and biochemical alterations associated withCSDS‐induced depression. Our results suggest that PPD exerts antidepressant‐like effects in mice with CSDS‐induced depression and that this effect may be mediated by the normalization of neurotransmitter and corticosterone levels and the alleviation of oxidative stress, as well as the enhancement of the PI3K/Akt/mTOR‐mediated BDNF/TrkB pathway.     

Protective effect of ginsenoside Rh2 on scopolamine‐induced memory deficits through regulation of cholinergic transmission,oxidative stress and the ERK‐CREB‐BDNF signaling pathway

Rh2 is a rare ginsenoside and there are few reports of its effect on cognition compared with other similar molecules. This study aimed to establish the impact of Rh2 treatment on improving scopolamine (Scop)‐induced memory deficits in mice and illuminate the underlying mechanisms. First, memory‐related behavior was evaluated using two approaches: object location recognition (OLR), based on spontaneous activity, and a Morris water maze (MWM) task, based on an aversive stimulus. Our results suggested that Rh2 treatment effectively increased the discrimination index of the mice in the OLR test. In addition, Rh2 elevated the crossing numbers and decreased the escape latency during the MWM task. Moreover, Rh2 markedly upregulated the phosphorylation of the extracellular signal‐regulated kinase (ERK)‐cAMP response element binding (CREB)‐brain derived neurotrophic factor (BDNF) pathway in the hippocampus. Meanwhile, the administration of Rh2 significantly promoted the cholinergic system and dramatically suppressed oxidative stress in the hippocampus. Taken together, Rh2 exhibited neuroprotective effects against Scop‐induced memory dysfunction in mice. Rh2 activity might be ascribed to several underlying mechanisms, including its effects on modulating the cholinergic transmission, inhibiting oxidative stress and activating the ERK‐CREB‐BDNF signaling pathway. Consequently, the ginsenoside Rh2 might serve as a promising candidate compound for Alzheimer's disease.     

Kaempferide prevents cognitive decline via attenuation of oxidative stress and enhancement of brain‐derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element‐binding signaling pathway

Kaempferide (KF) is a compound of flavonoids from Alpinae oxyphylla Miq, and the herb itself is used as a classical tonic agent. This paper aims to investigate the effects of KF on cognitive function impairment and neurodegeneration in the mouse model of Alzheimer's disease induced by intracerebroventricular (ICV) injection of Aβ_1–42. The mice were treated with KF at doses of 0.02 and 0.2 mg/kg/day (ICV) for five consecutive days after Aβ_1–42 exposures. The behavioral test results showed that KF could prevent cognitive decline in mice induced by Aβ_1–42 as assessed by the locomotor activity test, Y‐maze test, and Morris water maze test. Furthermore, the activities of superoxide dismutase and malondialdehyde in the hippocampus and cerebral cortex were elevated by KF administration. Results of hippocampus slices showed that neurons were integrated and regularly arranged in the groups, which were administered along with KF. In addition, we found KF could boost brain‐derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element‐binding (CREB) protein signal in the hippocampus. All results illustrated that KF could exert neuroprotective effects at least partly through alleviating oxidative stress and enhancing the BDNF/TrkB/CREB pathway in Aβ_1–42‐induced mice.     

天心解郁方对抑郁模型大鼠的作用及大脑内CAMP/PKA/CREB/BDNF信号通路的影响

目的：探索天心解郁方对抑郁模型大鼠的作用及大脑内CAMP/PKA/CREB/BDNF信号通路的影响。方法：雄性SD大鼠80只，剔除后随机分为空白组、模型组、天心解郁组、西药组、疏肝组、温肾组和疏肝健脾组7组，每组10只。除空白组外，其余组别按照慢性利血平诱导抑郁模型的方法造模28 d，造模前30 min给药，分别灌胃给药饮用水、天心解郁水煎液、氟西汀溶液、路优泰溶液、巴戟天寡糖胶囊溶液、舒肝解郁胶囊溶液，给药28 d后对各组大鼠的体质量、行为学指标、血清学细胞因子、脑组织相关靶点进行检测。结果：造模28 d后，与模型组相比，天心解郁组旷场实验水平运动得分、垂直运动得分和总路程的增加(P<0.05)，强迫游泳不动时间的缩短(P<0.001)，且较温肾组、疏肝组、疏肝健脾组更明显。与模型组相比，天心解郁组和温肾组可以增加大鼠血清内的CAMP含量(P<0.001, P<0.01)，其余组别则无明显变化(P>0.05)。与模型组相比，天心解郁组可以增加皮层内的PKA表达，促进海马内CREB、BDNF、ADRB2蛋白表达。与模型组相比，温肾组可以增加皮层内的PKA水平，其余组别无明显影响。结论：天心解郁方可能通过影响大脑内CAMP/PKA/CREB/BDNF信号通路，发挥抗抑郁作用，较单纯疏肝、温肾或疏肝健脾的方法，疗效更好，治疗靶点更多元化。     

Involvement of mTOR‐related signaling in antidepressant effects of Sophoraflavanone G on chronically stressed mice

SophoraflavanoneG (SG), an important prenylated flavonoid isolated from Sophoraalopecuroides.L, is effective for many illnesses. The present study was designed to investigate whether the compound could reverse depressive‐like symptoms and investigate its possible mechanisms. Chronic Unpredictable Mild Stress (CUMS) mice were treated with fluoxetine and SG. The immobility time in forced swimming test (FST) and tail suspension test (TST) were recorded. The levels of pro‐inflammatory cytokines and neurotransmitters in the hippocampus were evaluated. Furthermore, the protein expressions of PI3K, AKT, mTOR, p70S6K, BDNF, and Trkb in hippocampus were detected. Rapamycin, the selective mTOR inhibitor, was used to estimate the potential mechanism. As a result, after 7 days of SG treatment, the immobility time in FST and TST was declined obviously. The levels of IL‐6, IL‐1β, and TNF‐α in the hippocampus were significantly reduced, and the quantity of 5‐HT and NE was raised considerably in SG‐treated group compared with the CUMS‐exposed group. Additionally, SG could up‐regulate the expressions of PI3K, AKT, mTOR, 70S6K, BDNF, and Trkb. The blockade of mammalian target of rapamycin signaling blunted the antidepressant effect and reversed the up‐regulation of BDNF expression caused by SG. These findings suggested that SG treatment alleviated depressive‐like symptoms via mTOR‐mediated BDNF/Trkb signaling.     

Imperatorin ameliorates learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling in prenatally‐stressed female offspring

Prenatal stress (PS) can lead to impaired spatial learning and memory in offspring. Imperatorin (IMP) is a naturally occurring furanocoumarin with many pharmacological properties. However, the effects of IMP on cognitive impairment induced by PS and the underlying molecular mechanisms remain unclear. We investigated the protective effect of IMP treatment after PS on learning and memory deficits in female offspring at postnatal 60 days. After treating prenatally‐stressed offspring with IMP (15 and 30 mg/kg) for 28 days, we found that IMP increased body weight and ameliorated spatial learning and memory and working memory deficits in female offspring rats. Meanwhile, hippocampal Glu and serum corticosterone levels in prenatally‐stressed offspring were significantly decreased after IMP administration. Additionally, IMP treatment significantly increased BDNF, TrkB, CaMKII, and CREB mRNA expression in the hippocampus of offspring rats. Furthermore, PS‐mediated induction of RKIP protein and mRNA expression and glucocorticoid receptor protein expression in the hippocampus of offspring rats were significantly decreased by IMP treatment, and the protein expression of BDNF and TrkB and relative levels of p‐EKR/ERK, p‐CaMKIIα/CaMKIIα, and p‐CREB/CREB were remarkably increased after IMP treatment. Taken together, IMP can ameliorate PS‐induced learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling pathway and hypothalamic–pituitary–adrenal axis.     

电针对PSD大鼠前额叶和海马BDNF、CREB表达调控的影响

目的观察电针对卒中后抑郁(PSD)模型大鼠行为学以及前额叶和海马脑源性神经营养因子(BDNF)、环磷腺苷反应元件结合蛋白(CREB)表达调控的影响。方法将旷场实验得分相近的40只大鼠随机分为正常组、模型组、西药组和电针组,每组10只。正常组孤养不作任何处理。其他组采用线栓法大脑中动脉阻塞联合慢性不可预知温和应激法制备PSD模型。模型组给予2 mL 0.9%生理盐水灌胃,西药组给予2 mL盐酸氟西汀溶液灌胃,电针组大鼠选取百会、丰隆、太冲、三阴交穴针刺治疗,丰隆、太冲接电针治疗仪,共治疗21 d。观察大鼠行为学的改变及前额叶和海马BDNF、CREB、BDNF mRNA、CREB mRNA表达的变化。结果应激21 d后,模型组、西药组、电针组大鼠较正常组神经功能缺损评分明显升高,体质量下降,旷场实验水平和垂直得分降低,糖水消耗量降低(P<0.05)。治疗21 d后,西药组、电针组较模型组大鼠神经功能缺损评分降低,体质量增加,自发活动增多,对新环境探索能力增强,糖水消耗量增加(P<0.05)。模型组大鼠前额叶和海马BDNF、CREB、BDNF mRNA、CREB mRNA表达较正常组明显减少(P<0.05);电针组和西药组BDNF、CREB、BDNF mRNA、CREB mRNA的表达较模型组明显升高(P<0.05)。结论电针能明显促进PSD模型大鼠前额叶和海马BDNF、CREB的表达,改善抑郁行为。     

涤痰汤加味方对血管性痴呆大鼠行为学及PKA/CREB 信号通路的影响

目的研究涤痰汤加味方对血管性痴呆(VD)大鼠行为学、大鼠海马PKA/CREB信号通路的影响。方法将120只雄性SD大鼠随机分为空白组和造模组,空白组20只,造模组100只,空白组予普通饲料喂养,造模组以高脂饲料喂养复合颈总动脉结扎制作VD模型,将模型制作成功大鼠随机分为模型组、多奈哌齐组、活血组、涤痰汤原方组、涤痰汤加味组,每组18只,空白组和模型组每天灌胃等量的生理盐水,其他组给予相应药物连续灌胃4周。采用水迷宫检测大鼠的行为学,采用ELISA和Western Blot法检测大鼠海马区PKA/CREB信号通路相关因子表达。结果与空白组比较,模型组大鼠发现平台时间和游泳总路程明显增加(P<0.01)。与模型组比较,各给药组大鼠发现平台时间和游泳总路程均减少(P<0.05,P<0.01)。与涤痰汤原方组比较,活血组发现平台时间和游泳总路程增多(P<0.05,P<0.01),涤痰汤加味组发现平台时间和游泳总路程减少(P<0.05)。与空白组比较,模型组大鼠穿越平台次数、目标象限时间均明显减少(P<0.01),首次抵达平台时间明显延长(P<0.01)。与模型组比较,多奈哌齐组大鼠穿越平台次数增加(P<0.05),首次抵达平台时间明显缩短(P<0.01);涤痰汤原方组、涤痰汤加味组和活血组大鼠穿越平台次数、目标象限时间均增加(P<0.05,P<0.01),首次抵达平台时间明显缩短(P<0.01)。与空白组比较,模型组大鼠海马组织中环磷腺苷(cAMP)、蛋白激酶A(PKA)、环磷腺苷效应元件结合蛋白(CREB)、脑源性神经营养因子(BDNF)、神经生长因子(NGF)含量均明显降低(P<0.01);与模型组比较,各给药组大鼠海马组织内cAMP、PKA、CREB、BDNF、NGF含量均增高(P<0.05,P<0.01)。与涤痰汤原方组比较,活血组大鼠海马中cAMP、PKA、CREB、BDNF、NGF含量均减少(P<0.05,P<0.01),而涤痰汤加味组大鼠海马中cAMP、PKA、CREB、BDNF、NGF含量均增加(P<0.05)。结论涤痰汤加味可以改善VD模型大鼠的学习记忆能力,其机制可能与其激活海马PKA/CREB信号通路有关。     

Inulin‐Type Oligosaccharides Extracted from Yacon Produce Antidepressant‐Like Effects in Behavioral Models of Depression

Yacon (Smallanthus sonchifolius), a traditional food in the Andean diet, is attracting global attention for its medicinal properties, which are mainly because of its high content of non‐digestible oligosaccharides. The purpose of this study is to evaluate the antidepressant‐like effects of inulin‐type oligosaccharides extracted from yacon (YOs) in behavioral models of depression. Behavioral despair models in mice including the tail suspension test (TST) and the forced swimming test (FST) were used to determine the effects of acute YOs administration. The locomotor activity was also explored to eliminate any false‐positive activity. In addition, to further investigate the antidepressant‐like effects of subchronic YOs administration, the learned helplessness (LH) paradigm in rats was performed. The results demonstrated that YOs (25, 50, or 100 mg/kg, p.o.) treatment significantly reduced the immobility time in the mouse TST and FST in a U‐shaped, dose‐dependent manner, and showed no stimulatory effect on the locomotor activity. Furthermore, subchronic YOs (25, 50, or 100 mg/kg, p.o.) treatment significantly reversed the escape deficits in LH rats, including an increased number of escape failures and prolonged escape latency. These findings suggest that the inulin‐type oligosaccharides extracted from yacon may be a prospective natural source for antidepressants. Copyright © 2016 John Wiley & Sons, Ltd.     

Anti‐depressant Effects of Aqueous Extract from Acanthopanax senticosus in Mice

In this paper, the anti‐depressant effects of Acanthopanax senticosus extract (ASE) were studied using animal models of depression including the forced swimming and tail suspension tests. The anti‐depressive mechanism of ASE was explored by monitoring the levels of monoamine neurotransmitters including 5‐hydroxytrylamine (5‐HT), norepinephrine (NE), and dopamine (DA), as well as cAMP response element‐binding (CREB) protein expression in the whole brain of mice following the tail suspension test. Our results showed that intragastric administration of ASE at a dose of 2000 mg/kg for seven days significantly reduced the duration of immobility in both the forced swimming test and the tail suspension test. These results indicate that ASE possesses antidepressant‐like properties. Pre‐treatment with 2000 mg/kg of ASE for seven days significantly elevated the levels of 5‐HT, NE, and DA in the whole brain of mice. Moreover, ASE at doses of 1000 and 2000 mg/kg significantly up‐regulated the level of CREB protein. Taken together, these findings suggest that the anti‐depressive mechanism of ASE may be mediated via the central monoaminergic neurotransmitter system and CREB protein expression. Therefore, administration of ASE may be beneficial for patients with depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

基于cAMP-CREB-BDNF信号通路探讨交泰丸抗抑郁的作用机制

[目的]基于cAMP-CREB-BDNF信号通路探讨交泰丸抗抑郁作用机制。[方法]采用慢性温和不可预知性应激刺激建立大鼠抑郁症模型。酶联免疫吸附实验(ELISA法)检测大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)的含量和磷酸二酯酶-4(PDE4)的活性以及血浆中cAMP含量的变化,逆转录PCR法(RT-PCR)测定海马、皮质中的BDNF mRNA的含量。免疫组织化学分析大鼠海马组织CA1和CA3区中p-CREB阳性细胞的表达数量变化。[结果]与空白组相比,模型组的大鼠血浆及海马中cAMP含量明显降低,海马组织中CREB、BDNF含量降低,海马组织中PDE4活性增强,大鼠海马、皮质和下丘脑中BDNF mRNA表达含量减少,交泰丸逆转了以上改变。[结论]交泰丸可以通过调节cAMP-CREB-BDNF信号通路发挥抗抑郁作用。     

Neuroprotective effect of salidroside against central nervous system inflammation‐induced cognitive deficits: A pivotal role of sirtuin 1‐dependent Nrf‐2/HO‐1/NF‐κB pathway

Central nervous system (CNS) inflammation occurs in cognitive dysfunctions, but the underlying mechanisms remain unclear. Here, we investigated the role of sirtuin 1 (SIRT1) and salidroside in CNS inflammation‐induced cognitive deficits model. In vivo, CNS inflammation was initiated by a single intracerebroventricular injection of lipopolysaccharide (LPS). The levels of inflammatory cytokines and the capability of free radial scavenging were determined after the LPS challenge. In vivo, salidroside and nicotinamide, a SIRT1 inhibitor, were used in PC12 cell. Of note, with the treatment of salidroside, LPS‐induced learning and memory impairments were effectively improved. Salidroside also remarkably inhibited the inflammatory cytokines, up‐regulated the concentration of superoxide dismutase and inhibited the vitalities of malondialdehyde in serum, hippocampus, and cell supernatant. Besides, the expression of Sirt1, Nrf‐2, HO‐1, Bax, Bcl‐2, caspase‐9, and caspase‐3 and the phosphorylation of AMPK, NF‐κBp65, and IκBα were increased accompanying with the LPS‐induced cognitive impairments, which were significantly suppressed by salidroside treatment. In PC12 cell model, nicotinamide significantly abrogated the beneficial effects of salidroside, as indicated by the antioxidant, anti‐inflammatory, and antiapoptosis signaling. Together, our results showed that salidroside may be a novel therapy drug in neurodegenerative diseases, and the protective effect was involved in SIRT1‐dependent Nrf‐2/HO‐1/NF‐κB pathway.     

Ginseng Protein Reverses Amyloid Beta Peptide and H2O2 Cytotoxicity in Neurons,and Ameliorates Cognitive Impairment in AD Rats Induced by a Combination of D‐Galactose and AlCl3

Ginseng (Panax ginseng C.A. Meyer) is one of the most widely used herbal medicines worldwide. The present study evaluated the neuroprotective effects of ginseng protein (GP) and its possible mechanisms in a cellular and animal model of AD. The results demonstrated that GP (10–100 µg/mL) significantly improved the survival rate of neurons and reduced the cells' apoptosis and the mRNA expression of caspase‐3 and Bax/Bcl‐2. In addition, GP (0.1 g/kg) significantly shortened the escape latency, prolonged the crossing times and the percentage of residence time; reduced the level of Aβ_1–42 and p‐tau, the activity of T‐NOS and iNOS, and the content of MDA and NO, improved the activity of SOD, the concentration of cAMP and the protein expression of p‐PKA/PKA and ‐CREB/CREB. The results demonstrated that GP significantly inhibited Alzheimer‐like pathophysiological changes induced by Aβ_25–35 or H₂O₂ in cells or those induced by D‐gal/ Al in animals. These neuroprotective effects of GP may be associated with the cAMP/PKA/CREB pathway. Also, in combination with our previous studies, these results indicate that the anti‐AD mechanism of GP was likely to activate the CREB pathway through multiple channels. Copyright © 2016 John Wiley & Sons, Ltd.     

Schisandra chinensis ameliorates depressive‐like behaviors by regulating microbiota‐gut‐brain axis via its anti‐inflammation activity

The present study aimed to examine the antidepressant actions of the composition fractions of Schisandra chinensis using LPS‐induced mice. Animals were treated with total extracts (SCE), lignans (SCL), polysaccharides (SCPS), and essential oil (SCVO), and then subjected to behavioral tests. The forced swimming test (FST) and tail suspension test (TST) were used as predictive animal models of antidepressant activity. Total extracts and lignans significantly decreased the duration of immobility in FST and TST. We found that treatment with SCE and SCL could significantly decrease the levels of pro‐inflammatory cytokines both in the periphery and central nervous system (CNS). This was confirmed by the histopathological examination of the colon. The RT‐PCR results demonstrated that SCE and SCL could greatly inhibit the TLR4/NF‐κB/IKKα signaling pathway. In addition, the concentrations of Butyric acid and Propionic acid were upregulated by the administration, and the decreased diversity of intestinal microbiota and alterations of the relative proportions of Bacteroidetes and Firmicutes phylum members, Barnesiella and Lactobacillus genus members in LPS‐induced mice were restored as well. All results suggested that lignans is the effective fraction of S.chinensis to ameliorating depressive disorders, which its anti‐inflammation activity possibly involved in the bidirectional connection between gut microbiota and brain.     

复方柴归方超临界CO_2提取物调控cAMP信号通路的抗抑郁作用机制研究

目的从环磷酸腺苷(c AMP)信号通路角度探讨复方柴归方超临界CO_2提取物的抗抑郁作用机制。方法采用慢性温和不可预知应激(CUMS)程序对大鼠进行造模,以高、中、低剂量复方柴归方超临界CO_2提取物及文拉法辛为干预药物,检测各组大鼠海马组织中c AMP、蛋白激酶A(PKA)、环磷酸腺苷反应原件结合蛋白(CREB)、脑源性神经生长因子(BDNF)水平及其相应m RNA水平。结果与对照组比较,模型组大鼠海马组织中c AMP、PKA、p-CREB、BDNF水平显著下降(P0.05、0.01),复方柴归方干预后,与模型组比较,各剂量组c AMP、PKA、p-CREB、BDNF水平均出现回调(P0.05、0.01);同时,模型组大鼠海马组织中酪氨酸激酶B(TrkB)、PKA、p-CREB、BDNF的m RNA水平显著下降(P0.05、0.01),复方柴归方干预后,与模型组相比,各剂量组Trk B、PKA、p-CREB、BDNF的m RNA水平均出现回调(P0.05、0.01)。结论复方柴归方超临界CO_2提取物可通过调控c AMP-PKA-CREB-BDNF信号通路发挥抗抑郁作用。     

基于cAMP-CREB-BDNF通路探讨柴胡-白芍药对抗抑郁作用机制

目的基于cAMP-CREB-BDNF通路探讨柴胡-白芍药对抗抑郁的作用机制。方法建立慢性温和不可预知应激(CUMS)大鼠抑郁模型,ELISA法测定大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)和磷酸二酯酶抑制剂(PDE4)以及血浆中cAMP水平的变化,采用RT-PCR法测定海马、下丘脑和皮质中的BDNF mRNA的表达。结果与模型组相比,阳性药组、柴胡-白芍药对给药组可以不同程度地逆转大鼠海马组织及血浆中cAMP水平和大鼠海马组织中p-CREB、BDNF水平的降低。同时阳性药组、柴胡-白芍药对给药组能够增加大鼠海马、皮质和下丘脑中BDNF m RNA的表达。结论柴胡-白芍药对对CUMS大鼠模型具有明显的抗抑郁作用,并可以通过调节cAMP-CREB-BDNF通路而达到抗抑郁的作用。