Ashwagandha and Its Active Ingredient, Withanolide A, Increase Phosphorylation of TrkB in Cultured Hippocampal Neurons

Aims: To primary rat embryonic hippocampal neurons in culture, ashwagandha or one of its active ingredients, withanolide A were added in the presence or absence of nutrient supplementation and then assayed for activity of the BDNF receptor, TrkB. Study Design: Primary hippocampal neurons were cultured and grown in nutrient-rich or nutrient-poor medium. Ashwagandha or withanolide A were then be added to both types of media with or without an inhibitor of TrkB or either the PI-3K or MAPK pathway. Place and Duration of Study: Department of Biological Sciences, California State University, Los Angeles, CA, USA, between July 2021 and August 2022. Methodology: Rat embryos were removed by cesarean section from mother rats at 18 days’ gestation and the hippocampi of the former dissected, plated into culture dishes, and treated with the appropriate drug(s) (see Study Design above). After 4 days, neurons were harvested for Western blotting. Optical density of Western blot bands were quantified and statistically analyzed in a 2-way ANOVA, using a level of statistical significance at P < .05. Results: Under normal conditions (with N2 supplement), ashwagandha, but not withanolide A, increased phospho-TrkB immunoreactivity when compared to the effects of vehicle (controls, F(11, 24) = 22.48, P < .001), although withanolide A did not quite reach statistical significance (P = .069) when compared to that of the controlled condition. Likewise, under nutrient-deprived conditions, both ashwagandha and withanolide A also increased phosphorylation of TrkB when compared to that of vehicle-nutrient-deprived conditions (P < .0001). The same results were obtained in the presence of inhibitors of TrkB itself and the PI-3K (ashwagandha, P < .001; withanolide A, P < .001) and MAPK (ashwagandha, P = .027; withanolide A, P = .045) pathways. Conclusion: Ashwagandha or withanolide A activates TrkB, in nutrient-deprived hippocampal neurons, underscoring its role in neuronal survival signaling.

Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway / 中国中药杂志

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1β), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1β and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1β and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Condición física e inflamatoria antes de una intervención quirúrgica mayor abdominal / Physical and inflammatory condition before major abdominal quirurgical intervention

Introducción: El desacondicionamiento físico se asocia con disminución en la capacidad cardiorrespiratoria, aumento en el contenido de grasa corporal, e imbalances en respuesta inflamatoria, todos ellos factor de riesgo frente a la agresión de una intervención quirúrgica mayor. El valor de consumo de oxígeno (VO2max), el índice de masa corporal (IMC) y los valores plasmáticos de citoquinas de pacientes programados para una intervención quirúrgica mayor abdominal a menudo no se tienen en cuenta en la valoración prequirúrgica. Objetivo: Determinar la condición física e inflamatoria de pacientes que se trataron con una intervención quirúrgica mayor abdominal. Métodos: Investigación cuantitativa, descriptiva. Muestra por conveniencia de pacientes que se trataron con una intervención quirúrgica mayor abdominal en dos hospitales de Manizales (Colombia). Previo a la intervención, se midió VO2max, el IMC y valores de citoquinas. Resultados: Participaron en el estudio 6 hombres y 48 mujeres. Los valores promedio del VO2max se categorizaron como bajos. Se encontraron valores altos de IMC, del receptor antagonista de IL-1 (IL-1 Ra) y del factor neutrotrófico derivado del cerebro (BDNF). No se hallaron diferencias significativas en los valores promedio de VO2max, de IL-1Ra y de BDNF entre los grupos. Los pacientes programados para intervención quirúrgica ginecológica y gastrointestinal tuvieron sobrepeso y los programados para intervención quirúrgica bariátrica fueron obesos mórbidos. Conclusión: Pacientes programados para una intervención quirúrgica mayor abdominal presentan valores bajos de VO2max para la edad y altos de IMC. Se hallaron valores altos de IL-1Ra y de BDNF asociadas a obesidad y a posible antiinflamación(AU)

Introduction: Physical deconditioning is associated with, a decrease in cardiorespiratory capacity, an increase in body fat content and imbalances in the inflammatory response, all of which are risk factors for the aggression of a major surgical intervention. The oxygen consumption value (VO2max), body mass index (BMI), and plasma cytokine values of patients scheduled for major abdominal surgery are often not taken into account in the presurgical evaluation. Objective: To determine the physical and inflammatory condition of patients who were treated with a major abdominal surgery. Methods: Quantitative, descriptive research. Convenience sample of patients who underwent major abdominal surgery in two hospitals in Manizales (Colombia). Prior to the intervention, VO2max, BMI and cytokine values were measured. Results: 6 men and 48 women participated in the study. Average VO2max values were categorized as low. High values of BMI, IL-1 receptor antagonist (IL-1 Ra) and brain derived neutrotrophic factor (BDNF) were found. No significant differences were found in the mean VO2max, IL-1Ra and BDNF values between the groups. Patients scheduled for gynecological and gastrointestinal surgery were overweight and those scheduled for bariatric surgery were morbidly obese. Conclusion: Patients scheduled for major abdominal surgery have low VO2max values for age and high BMI. High IL-1Ra and BDNF values were found associated with obesity and possible anti-inflammation(AU)

Blood levels of brain-derived neurotrophic factor (BDNF) in systemic lupus erythematous (SLE): a systematic review and meta-analysis

Abstract Objectives BDNF has been implicated in the pathophysiology of systemic lupus erythematosus (SLE), especially its neuropsychiatric symptoms. The purpose of this study was to investigate the profile of blood BDNF levels in patients with SLE. Methods We searched PubMed, EMBASE, and the Cochrane Library for papers that compared BDNF levels in SLE patients and healthy controls (HCs). The Newcastle-Ottawa scale was used to assess the quality of the included publications, and statistical analyses were carried out using R 4.0.4. Results The final analysis included eight studies totaling 323 healthy controls and 658 SLE patients. Meta-analysis did not show statistically significant differences in blood BDNF concentrations in SLE patients compared to HCs (SMD 0.08, 95% CI [− 1.15; 1.32], P value = 0.89). After removing outliers, there was no significant change in the results: SMD -0.3868 (95% CI [− 1.17; 0.39], P value = 0.33. Univariate meta-regression analysis revealed that sample size, number of males, NOS score, and mean age of the SLE participants accounted for the heterogeneity of the studies (R2 were 26.89%, 16.53%, 18.8%, and 49.96%, respectively). Conclusion In conclusion, our meta-analysis found no significant association between blood BDNF levels and SLE. The potential role and relevance of BDNF in SLE need to be further examined in higher quality studies.

Serum plasminogen activator inhibitor-1 levels in patients with major depressive disorder vs. healthy controls: a systematic review and meta-analysis

Abstract Introduction Major depressive disorder (MDD) is a severe mental health condition that affects millions of people worldwide. Etiologically, several factors may play a role in its development. Previous studies have reported elevated plasminogen activator inhibitor-1 (PAI-1) levels in patients with depression, suggesting that PAI-1 levels might be linked to the etiology of MDD. Methods We systematically searched the following online databases: MEDLINE, Scopus, and Web of Science up to September 10, 2020, to identify studies in which PAI-1 levels were reported in subjects with MDD. Subsequently we used RevMan 5.3 to perform a meta-analysis of data extracted from the included studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PICO criteria for the search and analysis. Results Six studies that reported mean ± standard deviation (SD) were included in the analysis, with a total of 507 MDD patients and 3,453 controls. The overall standardized mean difference (SMD) was 0.27 (95% confidence interval [95% CI] 0.01-0.53). PAI-1 serum levels were 0.27 SDs higher in MDD patients than in controls. The test for overall effect was significant (z = 2.04, p = 0.04). Substantial heterogeneity was detected among the studies, demonstrated by the inconsistency test (I2 = 72%) and the chi-square test (χ2 = 18.32; p = 0.003). Conclusion This systematic review and meta-analysis showed that MDD might be related to elevated PAI-1 levels. We propose larger prospective clinical studies to further investigate this clinical correlation and validate the clinical significance of these observations.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial

Abstract Objectives Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Oxidative stress and inflammatory process in borderline personality disorder (BPD): a narrative review

Borderline personality disorder (BPD) is a severe psychiatric condition that affects up to 2.7% of the population and is highly linked to functional impairment and suicide. Despite its severity, there is a lack of knowledge about its pathophysiology. Studies show genetic influence and childhood violence as factors that may contribute to the development of BPD; however, the involvement of neuroinflammation in BPD remains poorly investigated. This article aimed to explore the pathophysiology of BPD according to the levels of brain-derived neurotrophic factor (BDNF), inflammatory cytokines, and oxidative stress substances that exacerbate neuronal damage. Few articles have been published on this theme. They show that patients with BPD have a lower level of BDNF and a higher level of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in peripheral blood, associated with increased plasma levels of oxidative stress markers, such as malondialdehyde and 8-hydroxy-2-deoxyguanosine. Therefore, more research on the topic is needed, mainly with a pre-clinical and clinical focus.

Ginsenoside Rg1 injection combined with inosine tablets and vitamin B1 for the treatment of primary retinitis pigmentosa / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the effects of ginsenoside Rg1 injection combined with inosine tablets and vitamin B1 on serum brain-derived neurotrophic factor(BDNF), pituitary adenylate cyclase activating polypeptide(PACAP)and clinical efficacy in primary retinitis pigmentosa.METHODS: A total of 50 patients(100 eyes)with primary retinitis pigmentosa who admitted to the Department of Ophthalmology, the Second Affiliated Hospital of Hebei North University from August 2019 to March 2022 were selected as the research object. They were divided into the study group and the control group according to random number table, with 50 eyes in each group. Patients in the control group were treated with inosine tablets and vitamin B1, while patients in the study group were treated with ginsenoside Rg1 injection on the basis of the control group. The expression of BDNF and PACAP in serum, electroretinogram and spectral-domain optical coherence tomography(SD-OCT)were compared before and after treatment, and the retinal thickness(RT), mean deviation(MD), clinical efficacy and safety indexes were compared between the two groups.RESULTS: There were no differences in the MD of the two groups before treatment(t=1.670, P=0.098), while the MD of the study group was significantly lower than that of the control group after treatment(t=3.628, P&#x003C;0.01). Before treatment, RT with a diameter of 1mm at the circle of macular fovea was compared between the two groups(t=0.108, P=0.914), it was significantly higher than that in the control group after treatment(t=6.125, P&#x003C;0.01). Before treatment, there was no significant difference in the results of dark adaptation of electroretinogram between the two groups(all P&#x003E;0.05). After treatment, the results of dark adaptation in the study group were significantly better than those in the control group(all P&#x003C;0.01). Before treatment, there was no significant difference in the results of electroretinogram adaptation between the two groups(all P&#x003E;0.05). After treatment, the results of electroretinogram adaptation in the study group were significantly better than those in the control group(all P&#x003C;0.01). There was no significant difference in BDNF and PACAP between the two groups before treatment(all P&#x003E;0.05). BDNF and PACAP in the study group were higher than those of the control group after treatment(all P&#x003C;0.01). After treatment, no adverse reactions were observed in both groups.CONCLUSION: The treatment of patients with primary retinitis pigmentosa with ginsenoside will improve the retinal function and promote the prognosis of the disease by regulating the expression of BDNF and PACAP, and it is highly safe.

Epigenetic alteration of BDNF gene, social and health status as predictors of food and nutrition insecurity among familiar coffee farmers / Alteração epigenética no gene BDNF, status social e de saúde como preditores da insegurança alimentar e nutricional em cafeicultores familiares

ntroduction: state of Food and Nutritional Security (FNS) is one that should guarantee the right of permanent access to quality food and in sufficient quantity without prejudicing access to other basic rights. In Brazil, rural family farming establishments represent 84.4% of total agricultural establishments and contribute to more than 70% of all food consumed by Brazilians. In this context, the production of the coffee commodity stands out. However, despite being food producers, they do not earn a good income. Slow economic activity can lead to loss of wages and income, illness, as well as food insecurity (FNiS). In addition, the molecular effects of FNiS are poorly studied, especially epigenetic.Objective: the objective of the present study is to analyze the association between Brain-Derived Neurotrophic Factor (BDNF) DNA methylation and socio demographic, lifestyle, and epigenetic factors, among coffee farmers in the Caparaó zone, in Espirito Santo, Southeast Brazil.Methods: the study was carried out in 22 randomly selected coffee producing communities in Zona Caparaó, an area that produces coffee of recognized quality. A total of 570 coffee farming households, 18 to 60 years of age, were included in the study by answering a questionnaire about socioeconomic characteristics, land use and ownership, behavior, health, and working conditions. FNiS evaluation was carried out using the Brazilian Food Insecurity Scale. BDNF exon I methylation was examined by methylation-specific PCR. Body mass index and biochemical analyses were performed. Logistic regression models were used to verify factors associated with FNiS (p<0.05). Data were analyzed using the Stata® statistical software package version 14.Results: the FNiS prevalence found was 23.68%. In multivariable logistic regression, the occurrence of FNiS was associated with hypermethylation of exon I of the BDNF promoter exon I [ORa = 5.03 (95% (1.98, 12.82)] when compared to the unmethylated gene. Moreover, FNiS was associated with excessive workload [ORa = 3.36 (1.23, 9.22)], possession of less land (hectares) [ORa = 0.77 (0.67, 0.90)] and greater number symptoms and / or illnesses in real life [ORa = 1.12 (1.04.1.20)].Conclusion: there is a high prevalence of Food Insecurity in the studied region. This phenomenon was associated with epigenetic factors (BDNF methylation), excessive workload, small land ownership and a greater number of diseases / symptoms. Food insecurity is a psychosocial stressor that can lead to epigenetic changes in the BDNF gene, responsible for regulating cognitive functions, neuronal survival and involved in the genesis of psychiatric diseases.

Introdução: o Estado de Segurança Alimentar e Nutricional (SAN) é aquele que deve garantir o direito de acesso permanente à alimentação de qualidade e em quantidade suficiente sem prejudicar o acesso a outros direitos básicos. No Brasil, os estabelecimentos de agricultura familiar rural representam 84,4% do total de estabelecimentos agropecuários e contribuem com mais de 70% de todos os alimentos consumidos pelos brasileiros. Nesse contexto, destaca-se a produção da commodity café. No entanto, apesar de serem produtores de alimentos, não auferem bons rendimentos. A lenta atividade econômica pode levar à perda de salários e renda, doenças e insegurança alimentar (INSAN). Além disso, os efeitos moleculares da INSAN são pouco estudados, sobretudo epigenéticos.Objetivos: o objetivo do presente estudo é analisar a associação entre a metilação do promotor do BDNF e a INSAN e a associação da INSAN com fatores sociodemográficos, de estilo de vida e epigenéticos, em cafeicultores da zona do Caparaó, no Espírito Santo, Sudeste do Brasil.Método: o estudo foi realizado em 22 comunidades cafeeiras selecionadas aleatoriamente na Zona do Caparaó, área que produz café de reconhecida qualidade. Um total de 570 famílias de cafeicultores, entre 18 a 60 anos, foram incluídos no estudo e responderam a um questionário sobre características socioeconômicas, uso e posse da terra, hábitos de vida, saúde e condições de trabalho. A avaliação da INSAN foi realizada por meio da Escala Brasileira de Insegurança Alimentar. A metilação do éxon I do BDNF foi examinada por PCR específica para metilação. Índice de massa corporal e análises bioquímicas foram realizadas. Modelos de regressão logística foram utilizados para verificar os fatores associados à INSAN (p<0,05). Os dados foram analisados usando o software estatístico Stata® versão 14.Resultados: a prevalência de INSAN encontrada foi de 23,68%. Na regressão logística multivariada, a ocorrência de INSAN foi associada a hipermetilação do éxon I do promotor do gene BDNF [ORa = 5,03 (95% (1,98, 12,82)] quando comparado ao gene não metilado. Além disso, a INSAN foi associada a carga de trabalho excessiva [ORa = 3,36 (1,23, 9,22)], posse de menos hectares de terra [ORa = 0,77 (0,67, 0,90)] e maior número de sintomas e/ou doenças da vida real [ORa = 1,12 (1.04.1.20)].Conclusão: o estudo mostrou uma alta prevalência de Insegurança Alimentar na região analisada. Esse fenômeno foi associado a fatores epigenéticos (metilação do gene BDNF), carga horária excessiva, pequena propriedade de terra e maior número de doenças/sintomas. A INSAN pode ser um estressor capaz de promover alterações epigenéticas no gene BDNF, importante gene regulador da cognição, crescimento e sobrevivência neuronal e envolvido com doenças psiquiátricas.

Validation of the Brazilian version of the child pain catastrophizing scale and its relationship with a marker of central sensitization

Abstract Objectives The Pain Catastrophizing Scale-Child version (PCS-C) allows to identify children who are prone to catastrophic thinking. We aimed to adapt the Brazilian version of PCS-C (BPCS-C) to examine scale psychometric properties and factorial structure in children with and without chronic pain. Also, we assessed its correlation with salivary levels of Brain-Derived Neurotrophic factor (BDNF). Methods The Brazilian version of PCS-C was modified to adjust it for 7-12 years old children. To assess psychometric properties, 100 children (44 with chronic pain from a tertiary hospital and 56 healthy children from a public school) answered the BPCS-C, the visual analogue pain scale, and questions about pain interference in daily activities. We also collected a salivary sample to measure BDNF. Results We observed good internal consistency (Cronbach's value = 0.81). Parallel analysis retained 2 factors. Confirmatory factor analysis of our 2-factor model revealed consistent goodness-of-fit (IFI = 0.946) when compared to other models. There was no correlation between visual analogue pain scale and the total BPCS-C score; however, there was an association between pain catastrophizing and difficulty in doing physical activities in school (p= 0.01). BPCS-C total scores were not different between groups. We found a marginal association with BPCS-C (r= 0.27, p= 0.01) and salivary BDNF levels. Discussion BPCS-C is a valid instrument with consistent psychometric properties. The revised 2-dimension proposed can be used for this population. Children catastrophism is well correlated with physical limitation, but the absence of BPCS-C score differences between groups highlights the necessity of a better understanding about catastrophic thinking in children.

The grey matter volume and fractional amplitude of low-frequency fluctuation alterations in cerebral small vessel disease patients with subcortical ischemic depression and their relationship with brain derived neurotrophic factor gene polymorphism / 中华神经科杂志

Objective:To investigate the relationship between brain derived neurotrophic factor (BDNF) gene polymorphism and the change of grey matter volume (GMV) and fractional amplitude of low-frequency fluctuation (fALFF) in cerebral small vessel disease (CSVD) patients with subcortical ischemic depression (SID).Methods:Eighty-seven CSVD patients in the First Affiliated Hospital of Anhui Medical University were enrolled from July 2017 to November 2020 and divided into CSVD-SID group [Geriatric Depression Scale (GDS) score>10] and CSVD-non - depression group (CSVD-ND group, GDS score≤10) according to GDS. Both GMV and fALFF were calculated based on structural and functional magnetic resonance imaging data, and the interactions between SID diagnosis and BDNF gene on brain function and structure alteration were explored.Results:GMV was significantly increased in the posterior default network (pDMN; such as posterior cingulate gyrus/precuneus and middle temporal gyrus) in the CSVD-SID group compared with the CSVD-ND group. On GMV property, significant interactions between BDNF gene and SID were found in the cuneus ( F=25.50, P<0.001), precuneus lobe ( F=13.61, P<0.001) and cerebellum ( F=17.23, P<0.001). In the aspect of fALFF, the brain functional activity in the superior frontal gyrus was significantly increased in the CSVD-SID group compared with that in the CSVD-ND group (0.363±0.648 vs -0.427±0.514,cluster size=48 voxels, t=5.63, P<0.001). But there was no significant interaction between diagnosis and BDNF genotype on brain function. Conclusions:Both the GMV and fALFF were increased in CSVD-SID, mainly located in the pDMN and frontal lobe. Significant interaction was found between CSVD-SID and BDNF genotype on GMV.

Neuroprotective effect and the mechanism of Shenzao jiannao oral liquid on Alzheimer ’s disease model mice / 中国药房

OBJECTIVE To study the neuroprotective effects of Shenzao jianna o oral liquid （SZJN）on Alzheimer ’s disease （AD）model mice and its mechanism. METHODS The mice were randomly divided into sham operation group ，model group ， Donepezil hydrochloride tablet group （0.65 mg/kg），SZJN low-dose ，medium-dose and high-dose groups （0.3，1.5 and 7.5 g/kg， calculated by crude drug quantity ），with 12 mice in each group ，half male and half female. Each group was given relevant medicine（intragastric administration of water at constant volume in sham operation group and model group ），twice a day ，for consecutive 28 d. On the 15th day of administration ，intracerebroventricular injection of β-amyloid 1-42（Aβ1-42）combined with intraperitoneal injection of scopolamine hydrobromide were used to induce AD model. Morris water maze was used to detect the learning and memory ability of mice. HE staining and Nissl staining were used to evaluate the pathological changes of brain tissue in mice. The levels of MDA and SOD in brain tissue of mice were detected. The phosphorylation level of cyclic adenosine monophosphate response element binding protein （CREB） and expression of brain-derived neurotrophic factor （BDNF） in hippocampal tissues were detected by Western blot. RESULTS Compared with sham operation group ，the escape latency of the model group was significantly prolonged ，and the number of crossing the platform and the percentage of residence time in the target quadrant were significantly reduced （P＜0.01）. The level of SOD in brain tissue ，the phosphorylation level of CREB and the expression level of BDNF in hippocampus decreased significantly （P＜0.01），while the level of MDA increased significantly （P＜ 0.01）. In hippocampal CA 1 area and cortical tissue ，nerve cells showed significantly decreased number ，the disordered arrangement and large gap ；the shape of nucleus was irregular and deeply stained ，and Nissl body was blurred ，loosely arranged and the number decreased. Compared with model group ，the escape latency of mice in each dose group of SZJN was significantly shortened ，and the times of crossing the platform and the percentage of residence time in the target quadrant were significantly jing- increased（P＜0.01）. Above indexes of brain tissue in mice were reversed sig nificantly in SZJN high-dose group （P＜0.01），and pathological damage of brain tiss ue was improved. CONCLUSIONS SZJN can significantly improve the learning and memory ability of AD model mice ，and alleviate the pathological injury and oxidative stress of brain tissue ，which may be related to the activation of CREB/BDNF signaling pathway.

Increase in serum brain-derived neurotrophic factor levels during early withdrawal in severe alcohol users

Abstract Introduction Changes in brain-derived neurotrophic factor (BDNF) have been linked to the neuroadaptative consequences of chronic alcohol use and associated with disease severity and prognosis. Few studies have evaluated the influence of drug withdrawal and clinical and sociodemographic data on BDNF levels in severe alcohol users. Objectives Our goals were (1) to evaluate variation in BDNF levels during alcohol withdrawal and, (2) to assess the influence of putative confounding factors on BDNF levels. Methods Our sample consists of 62 men with alcohol use disorder undergoing a detoxification process. Serum BDNF levels were measured using a commercial sandwich-ELISA kit, at two points: before and after the detoxification period. Results We found an increase in BDNF levels during alcohol withdrawal (25.4±9.6 at admission vs. 29.8±10.2 ng/ml at discharge; p < 0.001), even after controlling for potential confounders (positive family history, number of days between blood sample collections, and age) (Generalized Estimating Equation: coefficient = -4.37, 95% confidence interval [95%CI] -6.3; -2.4; p < 0.001). Moreover, individuals who had first-degree relative with alcohol dependence had smaller increases in BDNF levels than individuals with no family history (14.8 [95%CI -5.3; 35.6] vs. 35.3 [95%CI 15.4; 74.8]; p = 0.005). Conclusions In summary, variation in BDNF levels seems to be influenced by withdrawal in severe alcohol users. A positive family history of alcohol dependence could also be a factor that influences variation in this biomarker.

Total Flavones of Spatholobi Caulis Regulate Hippocampal Neuroplasticity in Depressed Rats Through CREB/BDNF Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of total flavones of Spatholobi Caulis （TFSC） against depression in rats. MethodThe fifty KM mice were randomly divided into the normal group and high-， medium-， and low-dose （1， 0.5， 0.25 g·kg-1） TFSC groups and gavaged with the corresponding drugs for 12 successive days. One hour after the last administration， the immobility time in forced swimming test and tail suspension test was recorded. The SD rats were randomly divided into the normal group， model group， fluoxetine （5 mg·kg-1） group， and high- and low-dose （1， 0.25 g·kg-1） TFSC groups. Following the exposure of rats to two different kinds of stimuli daily for inducing chronic unpredictable stress， they were administered with the corresponding drugs for 21 d. After the experiment， the levels of serum neurotransmitters and inflammatory factors in rats were detected by enzyme-linked immunosorbent assay （ELISA）. The changes in hippocampal neurons of rats were observed by hematoxylin-eosin （HE） and Nissl staining. The mRNA expression levels of nuclear factor-κB （NF-κB） and tumor necrosis factor-α （TNF-α） in the hippocampus of rats were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and the protein expression levels of cAMP-response element binding protein （CREB）， phosphorylated CREB （p-CREB）， and brain-derived neurotrophic factor （BDNF） in hippocampal tissues by Western blot. ResultCompared with the normal group， TFSC significantly shortened the immobility time of mice in tail suspension and swimming tests （P<0.05）. Compared with the normal group， the model group exhibited reduced sucrose intake and wilderness activity （P<0.01）， decreased 5-HT， DA， NE （P<0.05， P<0.01）， MAO， IL-6， TNF-α （P<0.05， P<0.01）， damaged neurons， increased mRNA levels of TNF-α and NF-κB （P<0.01）， and down-regulated BDNF and CREB protein expression （P<0.05）. Compared with the model group， TFSC significantly enhanced sucrose intake and wilderness activity of rats （P<0.05）， increased the serum 5-HT， DA and NE （P<0.05， P<0.01）， and decreased the serum MAO， IL-6， and TNF-α （P<0.05， P<0.01） as well as NF-κB and TNF-α mRNA expression （P<0.01）， up-regulated the protein expression levels of BDNF and CREB （P<0.01）， and improved the pathological symptoms of hippocampus. ConclusionTFSC improved the hippocampal neurons of rats via CREB/BDNF signaling pathway and reduced depressive pathological damage， thus relieving depression.

Dysfunctional eating behavior in fibromyalgia and its association with serum biomarkers of brain plasticity (BDNF and S100B): an exploratory study

ABSTRACT Objectives: To assess disordered eating, hunger and satiety perceptions in women with fibromyalgia (FM) compared to healthy controls (HC) and their association with biomarkers of brain plasticity (brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B)). Subjects and methods: Cross-sectional exploratory study. The sample included FM (n = 20) and HC (n = 19), matched to age and waist perimeter. Dysfunctional eating was assessed through the Three Factor Eating Questionnaire and Eating Disorders Examination with a questionnaire. Hunger and satiety levels were rated by a Numerical Scale. Serum leptin, S100B and BDNF were analyzed. Results: The MANCOVA analysis showed that the mean of Emotional Eating rates was 30.65% higher in FM compared to HC ( p = 0.015). Eating, shape and weight concerns were 77.77%, 57.14% and 52.22% higher in FM ( p = <0.001) compared to HC, respectively. Moreover, the FM group reported higher scores for feeling of hunger "[5.2 (±2.9) vs. 4.8 (±2.0); p = 0.042] and lower scores for satiety [7.0 (±1.7) vs . 8.3 (±1.0); p = 0.038]. In the FM group, serum BDNF was negatively associated with hunger (r = - 0.52; p = 0.02), while S100B was positively associated with hunger scores (r = 0.463; p = 0.004). Conclusion: The present findings support the hypothesis that the association between FM and obesity can be mediated by a hedonistic pathway. Further research is needed.

Effect and Mechanism of Chaihu Jia Longgu Muli Tang on Hippocampus of Rats with Chronic Stress Depression Based on BDNF/TrkB/CREB Pathway / 中国实验方剂学杂志

Objective:To explore the effect of Chaihu Jia Longgu Muli Tang on the hippocampus of rats with chronic stress depression based on the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB)/cyclic adenosine phosphate response element-binding protein (CREB) pathway. Method:Sixty SD rats were divided into a blank group (<italic>n</italic>=10) and an experimental group (<italic>n</italic>=50) for the induction of the chronic stress depression model. The rats in the experimental group were further divided into the following five groups: a model group， a fluoxetine hydrochloride group (0.003 g·kg^-1), and low-(1.625 g·kg^-1), medium-(3.25 g·kg^-1), and high-dose (6.5 g·kg^-1) Chaihu Jia Longgu Muli Tang groups. The rats were administered correspondingly by gavage once a day for eight weeks. Behavioral tests were performed to evaluate the depression state of the rats before modeling， after modeling， and after drug administration. Hematoxylin-eosin (HE) staining was used to observe the morphological changes in the hippocampus of rats. The immunohistochemical (IHC) staining was used to quantitatively detect BDNF protein expression in the rat hippocampus. The mRNA and protein expression of BDNF， TrkB， and CREB in the rat hippocampus was detected by the real-time fluorescence-based quantitative PCR (Real-time PCR) and Western blot， respectively. Result:Compared with the blank group， the model group showed decreased sucrose preference rate (<italic>P</italic><0.05)， declining horizontal and vertical scores (<italic>P</italic><0.05)， and prolonged immobility time and floating time (<italic>P</italic><0.05). Additionally， HE staining results revealed that hippocampal neuron structure was damaged. IHC staining showed that the mRNA and protein expression of BDNF， TrkB， and CREB was significantly decreased (<italic>P</italic><0.05). Compared with the model group， the fluoxetine hydrochloride group and the Chaihu Jia Longgu Muli Tang groups displayed elevated sucrose preference rate (<italic>P</italic><0.05)， increased horizontal and vertical scores (<italic>P</italic><0.05)， and shortened immobility time and floating time (<italic>P</italic><0.05). Furthermore, the hippocampal neuron structure was significantly repaired. IHC staining showed that the mRNA and protein expression of BDNF， TrkB， and CREB was significantly increased (<italic>P</italic><0.05). Conclusion:Chaihu Jia Longgu Muli Tang can significantly improve the depression-like behaviors of rats after chronic stress stimulation and enhance the regeneration and repair of neurons in the hippocampus. The underlying mechanism may be related to the up-regulation of the BDNF/TrkB/CREB signaling pathway in the hippocampus of rats.

Clinical Observation of Suanzaoren Tang Combined with Fluoxetine in Treatment of Depression of Liver Stagnation and Blood Deficiency Accompanied by Insomnia / 中国实验方剂学杂志

Objective:To observe the clinical therapeutic effect of Suanzaoren Tang combined with fluoxetine in the treatment of patients with depression of liver stagnation and blood deficiency accompanied by insomnia. Method:The patients with depression of liver stagnation and blood deficiency accompanied by insomnia （120 cases） were randomly divided into an observation group and a control group， with 60 cases in each group. The patients in the observation group received Suanzaoren Tang combined with fluoxetine， and those in the control group received fluoxetine. The course of treatment was eight weeks. The clinical efficacy was evaluated with Hamilton Depression Rating Scale （HAMD）， Pittsburgh Sleep Quality Index（PSQI）， and Activities of Daily Living （ADL） score. Enzyme-linked immunosorbent assay （ELISA） was used to determine the plasma levels of 5-hydroxytryptamine （5-HT）， norepinephrine （NE），brain-derived neurotrophic factor （BDNF）， glial cell-derived neurotrophic factor （GDNF）， neuron-specific enolase （NSE）， and S100<italic>β</italic>. Result:After eight weeks of treatment， the scores of HAMD and PSQI were reduced（<italic>P</italic><0.01）， while the scores of ADL were elevated（<italic>P</italic><0.01），and the levels of 5-HT， NE， GDNF and BDNF were up-regulated （<italic>P</italic><0.01） in the plasma of patients in the observation group as compared with those before treatment. After treatment， compared with the control group， the observation group showed increased total effective rate（<italic>P</italic><0.01）， decreased scores of HAMD and PSQI （<italic>P</italic><0.01）， elevated score of ADL（<italic>P</italic><0.01）， up-regulated levels of 5-HT， NE， GDNF and BDNF in plasma， and declining NSE and S100<italic>β</italic>（<italic>P</italic><0.01）. Conclusion:Suanzaoren Tang combined with fluoxetine is superior to fluoxetine alone in treating the depression of liver stagnation and blood deficiency accompanied by insomnia. Its therapeutic effect is achieved by increasing the release of monoamine neurotransmitters and promoting the secretion of BDNF and GDNF in the brain.

Effect of Sinisan on BDNF/TrkB， 5-HT/5-HT1AR， and HPA axis in Depression Model Rats / 中国实验方剂学杂志

Objective:To observe the effect of Sinisan on the brain-derived neurotrophic factor （BDNF）/tyrosine kinase receptor B （TrKB）， 5-hydroxytryptamine （5-HT）/5-HT1A receptor （5-HT1AR）， and hypothalamus-pituitary-adrenal （HPA） axis in depressed rats， and explore the antidepressant mechanism of Sinisan based on BDNF/TrKB， 5-HT/5-HT1AR， and HPA axis. Method:A total of 120 male Wistar rats were randomly divided into a normal group， a model group， a fluoxetine （0.01 g·kg^-1） group， and low- （1.25 g·kg^-1）， medium- （2.5 g·kg^-1）， and high-dose （5 g·kg^-1） Sinisan groups， with 20 rats in each group. The depression model was induced by isolation combined with chronic unpredictable mild stimulation（CUMS） in rats except for those in the normal group for 21 days. Rats were then treated correspondingly once a day for 21 days by gavage. Those in the normal group and the model group received an equal volume of normal saline. During the intervention， the model rats were stimulated continuously. The depressive state of CUMS model rats was evaluated by sucrose preference test and open field test. Enzyme-linked immunosorbent assay （ELISA） was used to determine the levels of corticotropin-releasing hormone （CRH）， adrenocorticotropic hormone （ACTH）， and corticosterone （CORT） in the plasma and BDNF and 5-HT levels in the hippocampal homogenate. The mRNA expression of hippocampal TrKB， 5-HT1AR， glucocorticoid receptor （GR）， and mineralocorticoid receptor （MR） was detected by real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR）. The protein expression of hippocampal TrKB， 5-HT1AR， GR， and MR was detected by Western blot. The histomorphological changes of the hippocampus were observed by hematoxylin-eosin （HE） staining. Result:Compared with the normal group， the model group showed decreased sucrose preference rate （<italic>P</italic><0.01）， reduced horizontal and vertical scores in the open field test （<italic>P</italic><0.01）， increased plasma content of CRH， ACTH， and CORT （<italic>P</italic><0.01）， declining content of BDNF and 5-HT in the hippocampus （<italic>P</italic><0.01）， dwindled mRNA and protein expression levels of TrKB， 5-HT1AR， and GR （<italic>P</italic><0.01）， elevated mRNA and protein expression of MR （<italic>P</italic><0.01）， and damaged hippocampal neurons revealed by HE staining. Compared with the model group， the groups with drug intervention showed increased sucrose preference rate （<italic>P</italic><0.01） and horizontal and vertical scores in the open field test （<italic>P</italic><0.05， <italic>P</italic><0.01）， decreased content of plasma CRH， ACTH， and CORT （<italic>P</italic><0.05， <italic>P</italic><0.01）， elevated content of hippocampal BDNF and 5-HT （<italic>P</italic><0.05， <italic>P</italic><0.01）， elevated mRNA and protein expression levels of hippocampal TrKB， 5-HT1AR， and GR （<italic>P</italic><0.05， <italic>P</italic><0.01）， reduced mRNA and protein expression levels of hippocampal MR （<italic>P</italic><0.05， <italic>P</italic><0.01）， and recovered hippocampal neurons as revealed by HE staining. Conclusion:Sinisan can exert a significant antidepressant effect by increasing hippocampal BDNF and 5-HT content， up-regulating TrKB， 5-HT1AR， and GR mRNA and protein expression， down-regulating MR mRNA and protein expression， inhibiting HPA axis hypertrophy， and enhancing the regeneration and repair of hippocampal neurons.

Effect and Mechanism of Qixian Tongluo Prescription on Neural Function Recovery in Patients with Cerebral Infarction / 中国实验方剂学杂志

Objective:To investigate the effect of Qixian Tongluo prescription on neural function recovery in patients with cerebral infarction and its mechanism. Method:A total of 100 inpatients （January to June，2020）with cerebral infarction in the Neurology Department of Wenzhou Hospital of Traditional Chinese Medicine were assigned to an experimental group （<italic>n</italic>=50） and a control group （<italic>n</italic>=50） according to the random number table. Both groups received conventional treatment of western medicine，while the experimental group took additional Qixian Tongluo prescription. Treatment lasted for 12 weeks. The clinical efficacy，National Institutes of Health Stroke Scale （NIHSS） score， the modified Barthel index （MBI），Fugl-Meyer assessment （FMA） score， and levels of brain-derived neurotrophic factor（BDNF），vascular endothelial growth factor（VEGF）， and stromal cell-derived factor-1（SDF-1） in peripheral blood of the two groups before and after treatment were compared. Result:The total response rate in the experimental group was 84.00%（42/50），higher than 66.00%（33/50） in the control group （<italic>Z</italic>=-7.365，<italic>P</italic><0.05）. There was no significant difference in the scores of MBI，FMA， and NIHSS before treatment between the two groups. The MBI and FMA scores of the two groups increased （<italic>P</italic><0.01）， and the NIHSS scores decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）. Compared with the control group after treatment， the experimental group showed increased MBI and FMA scores and decreased NIHSS score （<italic>P</italic><0.05）. There was no significant difference in BDNF level between the two groups before and after treatment. The VEGF and SDF-1 levels in the peripheral blood of the two groups were higher than those before treatment （<italic>P</italic><0.05）， and the experimental group was higher than the control group （<italic>P</italic><0.05）. Conclusion:Qixian Tongluo prescription can effectively improve the clinical efficacy，the quality of life， and the prognosis of patients with cerebral infarction during convalescence. The underlying mechanism is associated with the promotion of the expression of endogenous VEGF and SDF-1 in the peripheral blood to activate the SDF-1/chemokine receptor 4（CXCR4） signaling pathway， induce the recruitment and mobilization of endothelial progenitor cells， and facilitate the angiogenesis and repair of ischemic brain tissues.