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.     

Catalpol provides a protective effect on fibrillary Aβ1–42‐induced barrier disruption in an in vitro model of the blood–brain barrier

Excessive amyloid beta (Aβ) deposition in brain is mainly responsible for cell damage and blood–brain barrier (BBB) disruption in Alzheimer's disease (AD). Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch, has neuroprotective effect against AD. It is unclear whether catalpol has a protective effect on Aβ‐induced BBB leakage. We employed an immortalized endothelial cell line (bEnd.3) and astrocytes co‐culture to mimic a BBB model in vitro and investigated the effect of catalpol on BBB. We found that treatment with catalpol decreased BBB hyperpermeability induced by fibrillar Aβ_1–42. Data from western blotting showed that catalpol prevented fibrillar Aβ_1–42‐induced bEnd.3 cell apoptosis through mitochondria‐dependent and death receptor pathways; decreased the levels of matrix metalloproteinases (MMPs), MMP‐2, MMP‐9, and the receptor for advanced glycation end products; and increased the levels of tight junction proteins (ZO‐1, occludin, and claudin‐5), low‐density lipoprotein receptor‐related protein 1, and P‐glycoprotein in fibrillar Aβ_1–42‐treated bEnd.3 cells. Moreover, catalpol also enhanced soluble Aβ efflux across the fibrillar Aβ_1–42‐treated bEnd.3 cells BBB monolayer model. Altogether, our results suggest that catalpol alleviate fibrillar Aβ_1–42‐induced BBB disruption, enhance soluble Aβ clearance, and offer a feasible therapeutic application in AD treatment.     

Lavender and coriander essential oils and their main component linalool exert a protective effect against amyloid‐β neurotoxicity

Alzheimer's disease (AD) is a neurodegenerative disorder leading to cognitive deficits and cognitive decline. Since no cure or preventing therapy is currently available to counteract AD, natural‐derived compounds are investigated to find new potential neuroprotective agents for its treatment. In the present study, we tested the neuroprotective effect of lavender and coriander essential oils (EOs) and their main active constituent linalool, against the neurotoxicity elicited by Aβ_1‐42 oligomers, a key molecular factor in the neurodegeneration of AD. Importantly, our findings on neuronally differentiated PC12 cells exposed to Aβ_1‐42 oligomers are in accordance with previous in vivo studies reporting the neuroprotective potential of lavender and coriander EOs and linalool. We found that lavender and coriander EOs at the concentration of 10 μg/mL as well as linalool at the same concentration were able to improve viability and to reduce nuclear morphological abnormalities in cells treated with Aβ_1‐42 oligomers for 24 hours. Lavender and coriander EOs and linalool also showed to counteract the increase of intracellular reactive oxygen species production and the activation of the pro‐apoptotic enzyme caspase‐3 induced by Aβ_1‐42 oligomers. Our findings provide further evidence that these EOs and their main constituent linalool could be natural agents of therapeutic interest against Aβ_1‐42‐induced neurotoxicity.     

Decursin attenuates the amyloid‐β‐induced inflammatory response in PC12 cells via MAPK and nuclear factor‐κB pathway

Decursin, the major bioactive component of Angelica gigas Nakai, exhibited neuroprotective properties. Our previous studies showed that decursin conferred neuroprotective effects in PC12 cells induced by Amyloid‐β (Aβ)_25–35 via antiapoptosis and antioxidant. In this study, the antiinflammatory effects of decursin against PC12 cells injury stimulated by Aβ_25–35 were assessed. Our results demonstrated that decursin suppressed the expression of cyclooxygenase‐2 protein and prostaglandin E2 content which was stimulated by Aβ_25–35 in PC12 cells. Meanwhile, the nuclear translocation of nuclear factor‐κB in Aβ_25–35‐treated PC12 cells was also inhibited by decursin. In addition, decursin suppressed phosphorylation of the two upstream pathway kinases, p38 and c‐Jun N‐terminal kinase. Overall, our findings indicate that decursin exerts protective effects against neuroinflammation stimulated by Aβ_25–35 in PC12 cells by abolishing cyclooxygenase‐2 protein expression through inactivation of nuclear factor‐κB via the upstream kinases including p38 and c‐Jun N‐terminal kinase. This work provides a new insight into the pharmacological mode of decursin and should facilitate its therapeutic application in treatment of inflammatory disorders.     

The neuroprotective effects of an extract of Gastrodia elata

Ethnopharmacological relevance

Gastrodia elata (GE) Blume (family Orchidaceae) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, and epilepsy, indicating neuronal protective functions.

Aim of the study

To evaluate the neuroprotection of GE and its molecular mechanism in preventing serum deprivation-induced PC12 cell apoptosis.

Materials and methods

An MTT assay and Hoechst staining were used to respectively validate serum deprivation-induced cell death and apoptosis. Cyclic (c)AMP formation and protein kinase (PK)A activity were also measured after GE treatment. Western blotting was used to detect the phosphorylation of the cAMP response element-binding (CREB) protein. Transient transfection of a dominant negative CREB was used to validate the importance of CREB.

Results

GE targeted the adenosine A_2A receptor (A_2A-R). GE increased cAMP formation, PKA activity, and phosphorylation of the CREB protein. GE-induced CREB protein phosphorylation and protection was blocked by a PKA inhibitor and overexpression of the dominant negative CREB, respectively.

Conclusions

These results support the neuroprotective effects of GE. The protective mechanism might be mediated through an A_2A-R/cAMP/PKA/CREB-dependent pathway.     

Protective effects of dibenzocyclooctadiene lignans from Schisandra chinensis against beta‐amyloid and homocysteine neurotoxicity in PC12 cells

Aggregated beta‐amyloid (Aβ) and elevated plasma levels of homocysteine have been implicated as critical factors in the pathogenesis of Alzheimer's disease. The neuroprotective effects and possible mechanism of four structurally similar dibenzocyclooctadiene lignans (namely schisandrin, schisantherin A, schisandrin B and schisandrin C) isolated from the fruit of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) against Aβ_25‐35 and homocysteine toxicity in PC12 cells was studied. Exposure of PC12 cells to 0.5 µm Aβ_25‐35 caused significant cell death, increased the number of apoptotic cells, elevated reactive oxygen species, increased the levels of the pro‐apoptotic protein Bax and caspase‐3 activation. All these effects induced by Aβ_25‐35 were markedly reversed by schisandrin B and schisandrin C pretreatment, while schisandrin and schisantherin A had no obvious effects. Meanwhile, schisandrin B and schisandrin C reversed homocysteine‐induced cytotoxicity. The results indicated that schisandrin B and schisandrin C protected PC12 cells against Aβ toxicity by attenuating ROS production and modulating the apoptotic signal pathway through Bax and caspase‐3. Further structure–activity analysis of Schisandra lignans and evaluations of their neuroprotective effects using AD animal models are warranted. Copyright © 2010 John Wiley & Sons, Ltd.     

Alantolactone and Isoalantolactone Prevent Amyloid β25–35‐induced Toxicity in Mouse Cortical Neurons and Scopolamine‐induced Cognitive Impairment in Mice

Given the evidence for detoxifying/antioxidant enzyme‐inducing activities by alantolactone (AL) and isoalantolactone (IAL), the purpose of this study was to investigate the effects of AL and IAL on Aβ_25–35‐induced cell death in mouse cortical neuron cells and to determine their effects on scopolamine‐induced amnesia in mice. Our data demonstrated that both compounds effectively attenuated the cytotoxicity of Aβ_25–35 (10 μM) in neuronal cells derived from the mouse cerebral cortex. It was also found that the production of intracellular reactive oxygen species, including superoxide anion induced by Aβ_25–35, was inhibited. Moreover, the administration of the sesquiterpenes reversed scopolamine‐induced cognitive impairments as assessed by Morris water, Y‐maze, and the passive avoidance tests, and the compounds decreased acetylcholinesterase (AChE) activities in a dose‐dependent manner. Interestingly, AL and IAL did not improve scopolamine‐induced cognitive deficit in Nrf2 ^?/? mice, suggesting that memory improvement by sesquiterpenes was mediated not only by the activation of the Nrf2 signaling pathway but also by their inhibitory activity against AChE. In conclusion, our results showed that AL and IAL had neuroprotective effects and reversed cognitive impairments induced by scopolamine in a mouse model. Therefore, AL and IAL deserve further study as potential therapeutic agents for reactive oxygen species‐related neurodegenerative diseases. Copyright © 2017 John Wiley & Sons, Ltd.     

In vitro protective effects of Withania somnifera (L.) dunal root extract against hydrogen peroxide and β‐amyloid(1–42)‐induced cytotoxicity in differentiated PC12 cells

Withania somnifera L. Dunal (Solanaceae), also known as ‘ashwagandha’ in Sanskrit and as ‘Indian ginseng’, is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer, with antiaging, antistress, immunomodulatory and antioxidant properties. There is a paucity of data on the potential neuroprotective effects of W. somnifera root, as traditionally used, against H₂O₂‐ and Aβ_(1–42)‐induced cytotoxicity which are current targets for novel approaches to treat dementia, especially dementia of the Alzheimer's type (AD). In this study, an aqueous extract prepared from the dried roots of W. somnifera was assessed for potential protective effects against H₂O₂‐ and Aβ_(1–42)‐aggregated fibril cytotoxicity by an MTT assay using a differentiated rat pheochromocytoma PC12 cell line. The results suggest that pretreatments of differentiated PC12 cells with aqueous extracts of W. somnifera root significantly protect differentiated PC12 cells against both H₂O₂‐ and Aβ_(1–42)‐induced cytotoxicity, in a concentration dependent manner. To investigate the compounds that could explain the observed effects, the W. somnifera extract was analysed by liquid chromatography–serial mass spectrometry and numerous withanolide derivatives, including withaferin A, were detected. These results demonstrate the neuroprotective properties of an aqueous extract of W. somnifera root and may provide some explanation for the putative ethnopharmacological uses of W. somnifera for cognitive and other neurodegenerative disorders that are associated with oxidative stress. Copyright © 2010 John Wiley & Sons, Ltd.     

Protective effects of 4-geranyloxy-2,6-dihydroxybenzophenonel on DSS-induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF-κB signaling pathways

Hypericum sampsonii Hance has traditionally been used to treat enteritis and diarrhea. As one of the main benzophenones isolated from H. sampsonii, 4-geranyloxy-2,6-dihydroxybenzophenonel (4-GDB) has been shown to possess anti-inflammatory effects. However, the therapeutic effect and potential mechanisms of 4-GDB in ulcerative colitis (UC) remain unclear. This study aimed to evaluate the role of 4-GDB in UC using a dextran sulfate sodium-induced colitis mouse model. Intragastric administration of 4-GDB (20 mg/kg/day) for 8 days significantly attenuated colonic injury, reduced the expression of inflammatory mediators, and improved colonic barrier function in mice with colitis. Furthermore, in vivo and in vitro experiments indicated that 4-GDB could activate cAMP/PKA/CREB and inhibit the NF-κB pathway. Collectively, 4-GDB may be a potential agent for treating UC by regulating the cAMP/PKA/CREB and NF-κB pathways.     

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.     

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid β (Aβ), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti‐inflammatory effects, Aβ clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood–brain barrier penetrating compound, decreased Aβ deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti‐inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aβ reduction. Primary cultured cortical microglia were treated with Aβ_1–42, following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aβ_1–42‐induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aβ clearance through Aβ degradation enzymes after phagocytosis, we investigated the expression of Aβ degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aβ degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aβ degradation enzymes in M2 microglia, probably leading to Aβ plaque reduction.     

Genistein protects against amyloid‐beta‐induced toxicity in SH‐SY5Y cells by regulation of Akt and Tau phosphorylation

Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid‐β (Aβ) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aβ‐induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic‐acid differentiated SH‐SY5Y cells treated with different concentrations of Aβ_25–35 to investigate the effect of genistein against Aβ‐induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3β (GSK‐3β), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH‐SY5Y cells were pre‐treated for 24 hr with genistein (1 and 10 nM) and exposed to Aβ_25–35 (25 μM), and we found that genistein partially inhibited Aβ induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aβ‐induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aβ toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.     

下丘脑cAMP/PKA/PhK/GP通路在脾气虚食少腹胀中的作用研究

目的:通过观察下丘脑环磷酸腺苷(cyclic adenosine monophosphate, cAMP)/蛋白激酶A(protein kinase, PKA)/磷酸化蛋白激酶(phosphorylase kinase, PhK)/糖原磷酸化酶(glycogen phosphorylase, GP)通路的变化,从中枢糖原分解方面探讨脾气虚食少腹胀发生机制。方法:16只雄性SD大鼠按随机数字表法分为正常组和脾气虚组(模型组)各8只,代谢笼计量大鼠24 h进食水量,炭末推进法检测大鼠的胃残留率和小肠推进率,透射电镜观察下丘脑糖原颗粒情况,ELISA法检测下丘脑ATP、cAMP和PKA水平,Western blot法检测下丘脑PhK和GP表达。结果:与正常组比较,模型组大鼠进食水量减少,胃残留率增加,小肠推进率下降,下丘脑ATP、cAMP和PKA水平下降,下丘脑PhK、GP表达降低,差异有统计学意义。结论:脾气虚食少腹胀与cAMP-PKA-PhK-GP通路抑制所导致的下丘脑能量供给不足有关。     

Rapid antidepressant‐like effect of Fructus Aurantii depends on cAMP‐response element binding protein/Brain‐derived neurotrophic facto by mediating synaptic transmission

Several studies reported the relative antidepressant effects of Fructus Aurantii (FRA) with repeated treatment, the rapid antidepressant effects of FRA and the underlying mechanisms remained unclear. We, therefore, examined the rapid antidepressant actions of FRA in behavioral tests in mice and tested the underlying molecular mechanisms. We found FRA, like ketamine, reversed the behavioral deficits both in lipopolysaccharide(LPS)‐induced and learned helplessness (LH) models at 1 day after a single administration. FRA was also capable of increasing the expressions of protein kinase A/cAMP‐response element‐binding protein/brain‐derived neurotrophic factor (PKA/CREB/BDNF) signaling in hippocampus. Consistent with ketamine, FRA up‐regulated the expressions of GABAergic receptor (GAD67) and glutamatergic receptor 1 (GluR1) in mouse hippocampus both exposed to LPS and LH. Moreover, synaptic proteins such as postsynaptic density‐95 (PSD95) and synapsin1 were also up‐regulated by a single dose of FRA both in LH and LPS models, like ketamine. Finally, metadoxine (an antagonist of CREB) inhibited the antidepressant effects of FRA in tail suspension test (TST) and forced swimming test (FST) in LPS‐induced mice, which also blocked the phosphorylation of CREB and the expressions of neurotransmitters and synaptic molecules. Therefore, FRA had rapid antidepressant effects, which depended on PKA/CREB/BDNF pathway, subsequently regulated the downstream synaptic transmission.     

Silibinin protects rat pancreatic β‐cell through up‐regulation of estrogen receptors' signaling against amylin‐ or Aβ1–42‐induced reactive oxygen species/reactive nitrogen species generation

Amylin and amyloid‐β (Aβ) were found to induce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in rat pancreatic β‐cell line, INS‐1 cells, leading to cell death. In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) α and β (ERα and ERβ) and generation of ROS/RNS in amylin/Aβ_1–42‐treated INS‐1 cells. That is, pharmacological activation of ERs in INS‐1 cells significantly decreases ROS/RNS generation, but blockage of ERs increases ROS/RNS generation. Silibinin is a natural polyphenolic flavonoid isolated from milk thistle with phytoestrogen activities, also known as silybin. Treatment with silibinin down‐regulated ROS/RNS production induced by treatment with amylin/Aβ_1–42 in the cells. Silencing ERs expression with siRNAs targeting ERs showed that the protective effect of silibinin was markedly weakened, indicating that silibinin protection is largely attributed to activation of ERs' signaling. The binding of silibinin to ERs implies that the protective effect of silibinin on amylin/Aβ_1–42‐treated INS‐1 cells owes to down‐regulation of ROS/RNS through the activation of ERs phosphorylation. Amylin and Aβ_1–42 cotreatment enhanced furthermore ROS/RNS generation and cytotoxicity through further down‐regulation of ERs phosphorylation, and this was reversed by silibinin. Silibinin also protects INS‐1 cells from amylin and Aβ_1–42 cotreatment. These results indicate that protective effect of silibinin is mediated by enhancement of ERs phosphorylation that depresses ROS/RNS generation in amylin/Aβ_1–42‐treated INS‐1 cells.     

Two Alkaloids from Bulbs of Lycoris sanguinea MAXIM. Suppress PEPCK Expression by Inhibiting the Phosphorylation of CREB

In the fasting state, gluconeogenesis is upregulated by glucagon. Glucagon stimulates cyclic adenosine monophosphate production, which induces the expression of key enzymes for gluconeogenesis, such as cytosolic phosphoenolpyruvate carboxykinase (PEPCK‐C), which are involved in gluconeogenesis through the protein kinase A/cAMP response element‐binding protein (CREB) pathway. Using a luciferase reporter gene assay, a methanol extract of the bulbs of Lycoris sanguinea M_AXIM. var. kiushiana Makino was found to suppress cAMP‐enhanced PEPCK‐C promoter activity. In addition, two alkaloids, lycoricidine and lycoricidinol, in the extract were identified as active constituents. In forskolin‐stimulated human hepatoma cells, these alkaloids suppressed the expression of a reporter gene under the control of cAMP response element and also prevented increases in the endogenous levels of phosphorylated CREB and PEPCK mRNA expression. These results suggest that lycoricidine and lycoricidinol suppress PEPCK‐C expression by inhibiting the phosphorylation of CREB and may thus have the potential to prevent excessive gluconeogenesis in type 2 diabetes. Copyright © 2016 John Wiley & Sons, Ltd.     

Genistein inhibits Aβ25–35‐induced SH‐SY5Y cell damage by modulating the expression of apoptosis‐related proteins and Ca2+ influx through ionotropic glutamate receptors

In this study, we investigated the protective effects of genistein against SH‐SY5Y cell damage induced by β‐amyloid 25–35 peptide (Aβ_25–35) and the underlying mechanisms. Aβ‐induced neuronal death, apoptosis, glutamate receptor subunit expression, Ca²⁺ ion concentration, amino acid transmitter concentration, and apoptosis‐related factor expression were evaluated to determine the effects of genistein on Aβ‐induced neuronal death and apoptosis. The results showed that genistein increased the survival of SH‐SY5Y cells and decreased the level of apoptosis induced by Aβ_25–35. In addition, genistein reversed the Aβ_25–35‐induced changes in amino acid transmitters, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptors, and N‐methyl‐d ‐aspartate (NMDA) receptor subunits in SH‐SY5Y cells. Aβ_25–35‐induced changes in Ca²⁺ and B‐cell lymphoma‐2 (Bcl‐2) and Bcl‐2‐associated X (Bax) protein and gene levels in cells were also reversed by genistein. Our data suggest that genistein protects against Aβ_25–35‐induced damage in SH‐SY5Y cells, possibly by regulating the expression of apoptosis‐related proteins and Ca²⁺ influx through ionotropic glutamate receptors.     

牛蒡苷元干预CREB／BDNF信号通路保护Aβ25-35损伤神经元的研究

目的：探讨牛蒡苷元对β淀粉样肽（β-amyloid,Aβ）所致小鼠神经元损伤的保护作用。方法：从乳鼠大脑皮层分离、纯化神经元,制备Aβ25-35损伤神经元模型,采用MTT（四甲基偶氮唑盐）法检测牛蒡苷元（0、0．1、1、10、25、50μmol·L^-1）对受损神经元存活率的影响,用免疫荧光细胞化学法检测牛蒡苷元最佳浓度对受损神经元磷酸化环磷酸腺苷反应元件结合蛋白（p—CREB）水平和脑源性神经营养因子（BDNF）表达量的影响。结果：1μmol·L^-1牛蒡苷元能显著提高Aμ25-35损伤神经元的存活率,并使神经元的p—CREB和BDNF表达水平显著提高。结论：牛蒡苷元能够有效对抗Aμ诱导的神经元损伤,此作用可能与牛蒡苷元激活p—CREB／BDNF信号通路有关。     

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。     

Schisandrin C Ameliorates Learning and Memory Deficits by Aβ1–42‐induced Oxidative Stress and Neurotoxicity in Mice

Schisandrin C (SCH‐C) is a main and typical antioxidative lignan isolated from the fruits of Schisandra chinensis (Trucz.) Baill (a widely used traditional Chinese medicine). The present study aimed to characterize the effect of SCH‐C on memory impairment and further research on pathological changes in Aβ_1–42‐induced Alzheimer's disease mice. Mice were administration with SCH‐C daily for 5 days in the lateral cerebral ventricles using sterotaxically implanted cannula. Cognitive functions were assessed by Y‐maze test, active avoidance test and Morris water maze test in all groups, and the level of Aβ_1–42 and neuronal injury induced by Aβ_1–42 were reversed remarkably following SCH‐C treatment compared with sham group; meanwhile the impairment of short‐term or working memory was dramatically improved. In addition, SCH‐C significantly inhibited total cholinesterase (ChEtotal), and increased superoxide dismutase (SOD) and glutathione peroxidase (GSH‐px) activity glutathione (GSH) levels in the hippocampus and cerebral cortex. It can be speculated that SCH‐C offers protection against Aβ_1–42‐induced dysfunction in learning and memory by inhibiting ChEtotal and its antioxidant action. Copyright © 2015 John Wiley & Sons, Ltd.