Brain-derived neurotropic factor and GABAergic transmission in neurodegeneration and neuroregeneration

Neurotoxicity induced by stress,radiation,chemicals,or metabolic diseases,is commonly associated with excitotoxicity,oxidative stress,and neuroinflammation.The pathological process of neurotoxicity induces neuronal death,interrupts synaptic plasticity in the brain,and is similar to that of diverse neurodegenerative diseases.Animal models of neurotoxicity have revealed that clinical symptoms and brain lesions can recover over time via neuroregenerative processes.Specifically,brain-derived neurotropic factor（BDNF） and gamma-aminobutyric acid（GABA）-ergic transmission are related to both neurodegeneration and neuroregeneration.This review summarizes the accumulating evidences that suggest a pathogenic role of BDNF and GABAergic transmission,their underlying mechanisms,and the relationship between BDNF and GABA in neurodegeneration and neuroregeneration.This review will provide a comprehensive overview of the underlying mechanisms of neuroregeneration that may help in developing potential strategies for pharmacotherapeutic approaches to treat neurotoxicity and neurodegenerative disease.

Serum Levels of Brain-Derived Neurotrophic Factor in Patients with Obsessive-Compulsive Disorder in a Japanese Population

A role of lower brain-derived neurotrophic factor (BDNF) content in the pathogenesis of several mental illnesses has been suggested, especially in major depression. It is not known whether BDNF is involved in the pathogenesis of obsessive-compulsive disorder (OCD). Herein, we assessed the serum BDNF content and its correlation with symptom severity in a Japanese population with OCD. The serum BDNF levels of OCD patients (n = 39) and healthy controls (n = 37) were measured by ELISA. The severity of OCD symptoms was assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Beck Depression Inventory (BDI). The OCD patients’ BDNF levels were significantly higher than those of the controls (17.5 ± 7.3 vs. 12.7 ± 4.7) (p < 0.01). No correlation was observed between the OCD patients’ BDNF levels and their OCD symptoms as scored by the Y-BOCS. For all 76 subjects, the BDI scores were significantly negatively correlated with the serum BDNF levels. Our findings revealed that contrary to previous reports, the serum BDNF content in OCD patients could be higher than that of healthy subjects.

Synergistic effects of brain-derived neurotrophic factor and retinoic acid on inducing the differentiation of bone marrow stromal cells into neuron-like cells in adult rats in vitro

BACKGROUND： Under induction of retinoic acid （RA）, bone marrow stromal cells （BMSCs） can differentiate into nerve cells or neuron-like cells, which do not survive for a long time, so those are restricted to an application. Other neurotrophic factors can also differentiate into neuronal cells through inducing BMSCs; especially, brain-derived neurotrophic factor （BDNF） can delay natural death of neurons and play a key role in survival and growth of neurons. The combination of them is beneficial for differentiation of BMSCs. OBJECTIVE： To investigate the effects of BDNF combining with RA on inducing differentiation of BMSCs to nerve cells of adult rats and compare the results between common medium group and single BDNF group. DESIGN： Randomized controlled animal study SETTING： Department of Neurology, Affiliated Hospital of Xuzhou Medical College MATERIALS： The experiment was carried out in the Clinical Neurological Laboratory of Xuzhou Medical College from September 2003 to April 2005. A total of 24 SD rats, of either gender, 2 months old, weighing 130-150 g, were provided by Experimental Animal Center of Xuzhou Medical College [certification： SYXK （su） 2002-0038]. Materials and reagents： low-glucose DMEM medium, bovine serum, BDNF, RA, trypsin, separating medium of lymphocyte, monoclonal antibody of mouse-anti-nestin, neuro-specific enolase, glial fibrillary acidic protein （GFAP） antibody, SABC kit, and diaminobenzidine （DAB） color agent. All these mentioned above were mainly provided by SIGMA Company, GIBCO Company and Boshide Company. METHODS： Bone marrow of SD rats was selected for density gradient centrifugation. BMSCs were undertaken primary culture and subculture; and then, those cells were induced respectively in various mediums in total of 3 groups, including control group （primary culture）, BDNF group （20 μg/L BDNF） and BDNF＋RA group （20 μg/L BDNF plus 20 μg/L RA）. On the 3^rd and the 7^th days after induction, BMSCs were stained immunocytochemically with nestin （sign of nerve stem cells）, neuron-specific enolase （NSE, sign of diagnosing neurons） and GFAP （diagnosing astrocyte）, and evaluated cellular property. MAIN OUTCOME MEASURES ： Induction and differentiation in vitro of BMSCs in 3 groups RESULTS： （1） Induction and differentiation of BMSCs： Seven days after induction, cells having 2 or more apophyses were observed. Soma shaped like angle or erose form, which were similar to neurons and glial cells having strong refraction. （2） Results of immunocytochemical detection： Three days after induction, rate of positive cells in BDNF＋RA group was higher than that in BDNF group and control group [（86.15±4.58）%, （65.43±4.23）%, （4.18±1.09）%, P 〈 0.01]. Seven days after induction, rate of positive cells was lower in BDNF group and BDNF＋RA group than that in both groups at 3 days after induction [（31.12±3.18）%, （29.35±2.69）%, P 〈 0.01]; however, amounts of positive cells of NSE and GFAP were higher than those at 3 days after induction （P 〈 0.01）; meanwhile, the amount in BDNF＋RA group was remarkably higher than that in BDNF group （P 〈 0.01）. CONCLUSION： Combination of BDNF and RA can cooperate differentiation of BMSCs into neurons and astrocyte, and the effect is superior to single usage of BDNF.

The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that elicits neuronal survival and differentiation, synaptic transmission, and the modulation of synaptic plasticity. The biological actions of BDNF are mediated via two distinct receptors: the high-affinity tropomyosin-related kinase B (TrkB) receptor and the low-affinity p75 neurotrophin receptor (p75NTR). Recent findings regarding the actions and mechanisms of BDNF are reviewed here. Activity-dependent synaptic plasticity, as exemplified by long-term potentiation (LTP) and long-term depression (LTD), underlies the cellular mechanism of learning and memory. An accumulating body of evidence shows that BDNF modulates synaptic plasticity. This function requires extracellular neurotrophin release, synaptic activity-dependent local protein synthesis. In addition, a precursor of BDNF, proBDNF, is emerging as a new ligand with biological activities that are distinct from those of BDNF. The proteolytic cleavage of proBDNF is also proposed as a mechanism that determines the direction of BDNF actions. This review discusses the post-translational processing of proBDNF, the modulatory roles of the human BDNF polymorphism Val66Met, recent reports of the novel mechanisms of BDNF expression, and clinical reports showing the roles of BDNF in the blood. Taken together, these data provide new insights into the biological roles of BDNF and its related molecules in the central nervous system.

Research progress on brain-derived neurotrophic factor and non-suicidal self-injury addictive behavior associated with depressive disorders in adolescents

In recent years,non-suicidal self-injury(NSSI)behavior has emerged in a large number of adoles-cent depression.NSSI associated with adolescent depres-sion may be an addictive behavior,which has many sim-ilar neurobiological mechanisms to substance addiction.Brain-derived neurotrophic factor(BDNF)and precursor of BDNF(proBDNF)play an important role in addiction behavior,and they may be related to endogenous opioid receptors.The location and distribution of opioidμre-ceptors in the brain are related to reward,motivation and emotion regulated by behavioral addiction.The purpose of this paper is to review the general situation,mechanism and relationship between the characteristics of NSSI be-havior addiction and brain-derived nutritional factors in adolescents with depression.

Brain-derived neurotrophical factor after olfactory ensheathing cells transplantation in spinal cord injury of rats

Objective To observe the expression of brain - derived neurotrophical factor ( BDNF) in injury spinal cord after transplantation olfactory ensheathing cells ( OECs) , and to investigate the mechanism of OECs repairing spinal cord injury. Methods OECs from GFP transgenic rats were separated and cultured for transplantation. Spinal cord injury rats were separated two groups by

The roles of BDNF and ProBDNF in schizophrenia: possibilities for treatment

This review discusses the roles of brain-derived neurotrophic factor(BDNF)and precursor BDNF(proBDNF)in schizophrenia(SCZ).SCZ is asso-ciated with neuronal dysfunction,altered synaptic plas-ticity,and cognitive deficits.BDNF positively promotes neuronal growth,differentiation,and synapse forma-tion,and regulates synaptic transmission and plasticity.ProBDNF negatively affects neuronal survival and syn-aptic remodeling,however,by binding to its neurotroph-in receptor p75(p75NTR).A better understanding of the pathogenesis of SCZ vis-à-vis BDNF and proBDNF may provide new directions and strategies for its treatment.

松果菊苷对血管性痴呆大鼠学习记忆及海马组织BDNF、TrkB表达的影响

目的通过建立血管性痴呆(VD)大鼠模型,观察松果菊苷(ECH)对VD大鼠学习记忆及海马组织脑源性神经营养因子(BDNF)、酪氨酸激酶B(TrkB)表达的影响。方法取SD大鼠随机分为假手术组、模型组和ECH组(30 mg·kg^(-1)),每组30只。采用永久性结扎双侧颈总动脉建立大鼠VD模型,ECH组给予ECH治疗4周,采用Morris水迷宫检测学习记忆能力,处死大鼠取脑,分离皮层与海马组织,HE染色观察脑组织神经元损伤。RT-PCR法测定海马组织BDNF、TrkB mRNA表达,Western blot法检测BDNF、TrkB、AKT蛋白表达水平,免疫组化法测定N-甲基-D-天冬氨酸受体(NMDAR)蛋白的表达。结果与假手术组比较,模型组大鼠逃避潜伏期延长,穿越平台次数降低(P<0.05),脑组织皮质及海马组织神经元损伤明显,海马组织BDNF、TrkB mRNA表达及BDNF、TrkB、AKT、NMDAR蛋白表达低于假手术组(P<0.05);与模型组比较,ECH组大鼠逃避潜伏期缩短,穿越平台次数增加(P<0.05),脑组织皮质及海马组织神经元损伤明显改善,海马组织BDNF、TrkB的mRNA表达及BDNF、TrkB、AKT、NMDAR蛋白表达明显高于模型组(P<0.05)。结论松果菊苷可能通过上调VD大鼠海马区BDNF、TrkB、AKT、NMDAR表达,减轻VD大鼠神经元缺血损伤,改善学习记忆能力。

Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain unclear.It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke.Mounting evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced age.Previous studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model.Here,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic stroke.We found that as mice aged,Rac1 expression declined in the brain.Delayed overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–28.This was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by immunostaining.In a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells.Furthermore,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke.Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

HSP70被抗体封闭后对星形胶质细胞损伤后BDNF表达的影响

目的:探讨用抗体封闭热休克蛋白70(Heat shock protein70,HSP70)后对星形胶质细胞损伤后表达脑源性神经营养因子(Brain-derived neurotropic factor,BDNF)的影响。方法:原代培养并纯化星形胶质细胞,采用划痕损伤法构建细胞损伤模型,通过培养液内加入HSP70抗体来进行干预。在不同时间点对对照组和损伤干预组进行BDNF免疫细胞化学染色,观察细胞增生情况及BDNF的表达强度,并用RT-PCR检测BDNFmRNA的表达水平。结果:与对照组相比,干预组BDNF的表达明显减弱(P<0.05,P<0.01),GFAPmRNA的表达也明显降低(P<0.05,P<0.01)。结论:星形胶质细胞损伤后,HSP70可能具有促进星形胶质细胞表达BDNF的作用。

BDNF及其受体Trk B在低氧预适应小鼠中的表达变化和作用

目的探究BDNF、TrkB受体及BDNF/TrkB信号通路在急性低氧与低氧预适应小鼠中的表达变化及作用,进一步完善低氧预适应神经保护的分子机制,为低氧预适应的临床应用提供理论依据。方法以ICR小鼠为对象,分别构建急性低氧与低氧预适应小鼠模型,模型构建完成0～4 d后,通过Western blot、real-time PCR技术,检测小鼠海马脑区BDNF、TrkB受体在早期相和晚期相的表达及BDNF/TrkB信号通路活性的变化。结果研究发现随着小鼠低氧次数的增加,耐受时间明显增加(P<0. 05);较对照组,急性低氧和低氧预适应组BDNF及全长型TrkB受体表达有增加的趋势,在低氧预适应早期相BDNF蛋白水平表达显著增加(P<0. 05)。较对照组,截短型TrkB受体表达则有降低的趋势,在低氧预适应中、晚期相其mRNA表达显著降低(P<0. 05);较对照组,急性低氧组BDNF/TrkB信号通路活性被抑制,而低氧预适应组BDNF/TrkB信号通路活性有增加的趋势,且在晚期相差异有显著性(P<0. 05)。结论低氧预适应可能是通过上调BDNF表达并增加其与TrkB受体的结合,以及下调截短型TrkB受体表达,减少异二聚体形成,从而共同激活BDNF/TrkB信号通路,最终对小鼠产生神经保护作用。

低氧对BDNF和TrkB受体及其信号通路影响的研究进展

探析了急性低氧损伤与适度低氧或低氧预适应(HPC)神经保护作用的相关机制及其涉及的信号通路研究进展,回顾了脑源性神经营养因子(BDNF)、酪氨酸激酶受体B(TrkB)及BDNF/TrkB信号通路在神经生理及神经病理过程中的作用,并对急性低氧与低氧预适应分别影响BDNF、TrkB受体的表达和BDNF/TrkB信号通路的相关途径与机制进行了归纳。通过总结了解到低氧具有双重作用,既有严重缺氧导致损伤,又有适度低氧或低氧预适应对机体有益的保护作用,阐明其调节机制具有一定的参考价值。

BDNF对过敏性哮喘小鼠气道炎症影响的研究

目的探讨脑源性神经生长因子(BDNF)在过敏性哮喘小鼠肺组织中的变化,研究其对哮喘气道炎症及炎症相关因子白细胞介素-17A(IL-17A)、嗜酸性粒细胞趋化因子(Eotaxin)的影响,探索儿童哮喘发病的新机制。方法选取2019年10月至12月饲养于武汉市第一医院SPF级实验动物中心的C57/B6J小鼠。以随机数字表法将实验动物分为五组,每组8只,分别为A组:正常对照组;B1组:哮喘组(模型未干预组);B2组:哮喘+生理盐水干预组;B3组:哮喘+重组人BDNF干预组;B4组:哮喘+TrkB/Fc干预组。采用鸡卵清蛋白建立过敏性哮喘小鼠模型,运用重组人BDNF及其抑制剂TrkB/Fc进行干预,干预7天后处死小鼠。运用HE染色了解肺组织的炎症评分;用Western blot法检测肺组织中BDNF蛋白的表达;用ELISA法检测肺组织中IL-17A、Eotaxin蛋白的表达,并对其进行分析。结果①五组的肺组织病理评分比较差异有统计学意义(F=186.796,P<0.01);B1、B2、B3、B4组的病理评分均显著高于A组,B3组病理评分显著高于B1组,B4组病理评分显著低于B1组,B3组病理评分显著高于B2组,B4组病理评分显著低于B2组,B4组病理评分显著低于B3组,差异均有统计学意义(t=2.344~54.292,P<0.01)。②五组的肺组织中BDNF蛋白表达比较差异有统计学意义(F=216.173,P<0.01);B1、B2、B3组的BDNF蛋白表达均显著高于A组,B3组BDNF蛋白表达显著高于B1组,B4组BDNF蛋白表达显著低于B1组,B3组BDNF蛋白表达显著高于B2组,B4组BDNF蛋白表达显著低于B2组,B4组BDNF蛋白表达显著低于B3组,差异均有统计学意义(t=3.029~17.781,P<0.05)。③五组的IL-17A水平比较差异有统计学意义(F=322.192,P<0.01);B1、B2、B3、B4组的IL-17A水平均显著高于A组,B3组IL-17A水平显著高于B1组,B4组IL-17A水平显著低于B1组,B3组IL-17A水平显著高于B2组,B4组IL-17A水平显著低于B2组,B4组IL-17A水平显著低于B3组,差异均有统计学意义(t=2.038~58.122,P<0.05)。五组的Eotaxin水平比较差异有统计学意义(F=189.295,P<0.01);B1、B2、B3、B4组的Eotaxin水平均显著高于A组,B3组Eotaxin水平显著高于B1组,B4组Eotaxin水平显著低于B1组,B3组Eotaxin水平显著高于B2组,B4组Eotaxin水平显著低于B2组,B4组Eotaxin水平显著低于B3组,差异均有统计学意义(t=9.048~34.970,P<0.01)。结论BDNF对过敏性哮喘气道炎症的发生有促进作用,其机制可能通过诱导IL-17A、Eotaxin的释放,选择性地趋化和激活中性粒细胞、嗜酸性粒细胞、淋巴细胞等多种炎症因子的释放而扩大炎症效应,参与哮喘气道炎症的发生过程,这可能为儿童哮喘的病情评估及精准治疗提供思路。

Brain-derived neurotrophic factor protects neurons from GdCl_3-induced impairment in neuron-astrocyte co-cultures

Gadolinium (Gd3+) complexes are important contrast agents in medical magnetic resonance imaging (MRI) and of great potential value in brain research. In order to better understand the mechanisms of the action of Gd3+ on neurons in the complex central nervous system (CNS), the neurotoxic actions of GdCl3 have been investigated in both neuron monoculture and astrocyte-neuron co-culture systems. Measurements of lactate dehydrogenase release showed that GdCl3 causes significant cell death of monocultured neurons as a result of reactive oxygen species (ROS) generation and down-regulation of brain-derived neurotrophic factor (BDNF). However, GdCl3 does not affect the viability and BDNF expression of astrocytes. Both co-culturing of neurons with astrocytes and addition of BDNF ameliorated GdCl3-induced neurotoxicity by decreasing ROS generation and facilitating recovery of BDNF levels. The results obtained suggest that astrocytes in the CNS may protect neurons from GdCl3-induced impairment through secreting BDNF and thus up-regulating BDNF expression and interfering with Gd3+-induced cell signaling in neurons. A possible molecular mechanism is suggested which should be helpful in understand- ing the neurotoxic actions of gadolinium probes .

Correlation of prefrontal activity measured by near-infrared spectroscopy (NIRS) with mood, BDNF genotype and serum BDNF level in healthy individuals

Depression has been known to reduce the prefrontal activity associated with the execution of certain cognitive tasks, although whether a temporarily depressed or anxious mood in healthy individuals affects the prefrontal blood oxygen level during cognitive tasks is unknown. Combining the measurement of prefrontal activity with near-infrared spectroscopy (NIRS) and the two cognitive tasks, namely the letter version of the verbal fluency test (VFT-l) and the Stroop test, we measured the effect of a depressed or anxious mood and gender on the changes in the prefrontal oxygenated hemoglobin (Oxy-Hb) levels during those cognitive tests in healthy individuals. Depressed mood or anxious mood was assessed by the Hospital Anxiety and Depression Scale (HADS). Thereby we aimed to explore the possibility of NIRS measurement for detecting the early subclinical manifestation of major depression. Moreover, we examined the possible relationships between prefrontal activation and the functional Val66Met polymorphisms of the brain derived neurotropic factor (BDNF) gene and serum BDNF level. As a result, the increased prefrontal Oxy-Hb levels during cognitive tasks were significantly correlated with the severity of depressed mood in males. The course of the prefrontal Oxy-Hb increase was different depending on the cognitive tasks, i.e., the VFT-l or the Stroop test, in both genders. Correlations of BDNF genotype and serum BDNF level with the prefrontal Oxy-Hb levels during those cognitive tasks were negative. Our results suggest that the early subclinical manifestation of depressed mood in males might be detected by the NIRS measurement, which is not correlated with the individual properties of BDNF.

THE GENE EXPRESSION OF BDNF IN NORMAL RABBIT RETINA

Objective To investigate the distribution of bra in-derived neurotrophic factor(BDNF) protein in the rabbit retina. Methods Immune response material in the retina was observed using BDNF antibody by the method of immunohistochemistry. Results BDNF gene expression was mainly found in the RGCs, a lso in innernuclei cells and outernuclei cells in rabbit retina. Conclusion RGC is not only the target cell of BDNF, but also express the BDNF protein. BDNF from multi-sources participates in the regulati on of RGCs.

Research progress on whether BDNF can be used as a predictive biomarkerfor suicidal behavior

In recent years,the serious social phe-nomenon of suicide has been of great concern to society and academia.However,the study and early risk assess-ment of suicide have been limited by multiple aspects.Therefore,researchers have started to search for a reliable marker for early diagnosis of suicide risk,and one of the widely studied neurotransmitters associated with suicide is the brain-derived neurotrophic factor(BDNF).This re-view aims to summarize the current scientific knowledge on the relevance of BDNF and psychiatric disorders to suicide and to infer whether neurotrophic factors could be a reliable marker for early diagnosis of suicide risk.Based on the results of these studies,a link between BDNF and suicide may exist and act independently of mental illness.However,there is still controversy and further studies may provide researchers with useful information.

Research progress on the relationship between proBDNF and alcohol dependence and its related cognitive impairment

Brain-derived neurotrophic factor(BDNF)plays an important role in the growth,develop-ment,differentiation,injury,repair,survival and apoptosis of nerve cells.Precursor of BDNF(proBDNF)is an im-portant regulator of neurodegeneration,long-term hippo-campal inhibition and synaptic plasticity.Alcohol depen-dence syndrome(ADS)is a group of chronic recurrent diseases with unknown etiology.Current studies believe that proBDNF plays an important role in the occurrence,development and outcome of ADS.Alcohol dependence patients,like other neurodegenerative diseases,will also have different degrees of cognitive impairment.This arti-cle reviews the research progress on the relationship be-tween BDNF,proBDNF,alcohol dependence and cogni-tive impairment.

Research progress on BDNF in Sjogren's syndrome with depressive disorder

Brain-derived neurotrophic factor(BDNF)is a widely studied neurotrophic factor,which plays an important role in the growth,development,dif-ferentiation,injury,repair,survival and apoptosis of nerve cells.More and more studies have found that there is a high prevalence of depressive disorders in patients with autoimmune diseases.Sjogren's syndrome is a chronic autoimmune exocrine disease characterized by lympho-cytic infiltration and exocrine gland destruction.Depres-sive disorders are common in patients with Sjogren's syndrome.The quality of life of patients with Sjogren's syndrome with depression was generally lower than that of patients with Sjogren's syndrome without depres-sion.In this article,we reviewed the research progress of BDNF and depression in Sjogren's syndrome at home and abroad.

Role of BDNF in the taste system

Neurotrophins are a family of proteins that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins： NGF, BDNF, NT-3 and NT-4. Among them, BDNF is mostly studied in the taste system due to its high expression. Recent studies have shown BDNF play an important role in the developmental and mature taste system, by regulating survival of taste cells and geniculate ganglion neurons, and maintaining and guiding taste nerve innervations. These studies imply BDNF has great potentialities for therapeutic usage to enhance sensory regeneration following nerve injury, with aging, and in some neurodegenerative diseases.