Proprotein convertase 1/3-mediated down-regulation of brain-derived neurotrophic factor in cortical neurons induced by oxygen-glucose deprivation

Brain-derived neurotrophic factor(BDNF)has robust effects on synaptogenesis,neuronal differentiation and synaptic transmission and plasticity.The maturation of BDNF is a complex process.Proprotein convertase 1/3(PC1/3)has a key role in the cleavage of protein precursors that are directed to regulated secretory pathways;however,it is not clear whether PC1/3 mediates the change in BDNF levels caused by ischemia.To clarify the role of PC1/3 in BDNF maturation in ischemic cortical neurons,primary cortical neurons from fetal rats were cultured in a humidified environment of 95%N_2 and 5%CO_2 in a glucose-free Dulbecco's modified Eagle's medium at 37℃for3 hours.Enzyme-linked immunosorbent assays and western blotting showed that after oxygen-glucose deprivation,the secreted and intracellular levels of BDNF were significantly reduced and the intracellular level of PC1/3 was decreased.Transient transfection of cortical neurons with a PC1/3 overexpression plasmid followed by oxygen-glucose deprivation resulted in increased PC1/3 levels and increased BDNF levels.When levels of the BDNF precursor protein were reduced,the concentration of BDNF in the culture medium was increased.These results indicate that PC 1/3 cleavage of BDNF is critical for the conversion of pro-BDNF in rat cortical neurons during ischemia.The study was approved by the Animal Ethics Committee of Wuhan University School of Basic Medical Sciences.

Progress in the “brain-derived neurotrophic factor hypothesis of depression”

The traditional ＂brain-derived neurotrophic factor （BDNF） hypothesis of depression＂ proposes that impairment of the BDNF signaling pathway in the hippocampus and prefrontal cortex participates in the pathophysiology of depression, and antidepressants act by recovering/enhancing BDNF signal transduction. Recent studies have suggested that BDNF signaling pathways exert more diverse and complex effects on depression onset and antidepressant therapy than originally thought, which include： （1） inhibition of the BDNF-TrkB signaling pathway in the hippocampus and/or prefrontal cortex does not induce the depression-like behavioral phenotype, but significantly diminishes therapeutic effects, which suggests that the BDNF-TrkB signaling pathway lacks direct or key effects on occurrence of emotional disorders, whereas an intact and normal BDNF-TrkB signaling pathway is necessary for antidepressant therapy. （2） The BDNF-TrkB signaling pathway exhibits opposite regulatory effects on depressive behavior in the hippocampus-prefrontal cortex network and mesolimbic system, which suggests that BDNF regulates emotion by affecting the emotion-related neural network, but not a single brain region. （3） The BDNF-TrkB and proBDNF-p75Nm signaling pathways in the brain, respectively, enhance and suppress hippocampal neural plasticity, which demonstrated that different BDNF signaling pathways interact and restrict each other in the regulation of neural plasticity and emotional behaviors. （4） BDNF gene polymorphism might be associated with susceptibility to depression. These new findings extend our understanding of neuronal pathways and mechanisms of action of BDNF signaling and contribute to improved views to traditional ＂neurotrophic factor hypothesis of depression＂.

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.

基于BDNF-TrkB/proBDNF-p75^(NTR)信号通路探讨电针治疗脊髓损伤的分子机制

电针治疗脊髓损伤可以显著提高脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、原肌球蛋白受体激酶B(tropomyosin-receptor kinase,TrkB)蛋白的表达,下调p75神经营养素受体(p75 neurotrophin receptor,p75^(NTR))蛋白的表达。电针可以通过提高BDNF促进神经元的存活、促进受损纤维的再生、促进神经可塑性、促进髓鞘形成BDNF基因修饰的成纤维细胞。BDNF诱导的TrkB信号可能通过四种主要的细胞内途径影响突触可塑性、轴突生长、存活和细胞内阳离子平衡:(1)经磷脂酰-3激酶(P1-3K)/Akt通路促进神经元树突分枝和树突棘生成,影响突触生长和结构形成。(2)受体诱导小分子GTP酶Ras的激活,经过一系列复杂的磷酸化过程,最终激活许多细胞外信号调节激酶(extracellular signal-regulated Kinase,ERK)途径并对环腺苷3′,5′-单磷酸含量进行调节促进轴突生长。(3)经磷脂酶C-γ(Phospholipase C-γ,PLC-γ)/肌醇3-磷酸(inositol triphosphate,IP-3)通路参与Ca^(2+)的调控,促进Ca^(2+)从细胞内储存释放,促进突触可塑性等。(4)此外通过N-甲基-D-天冬氨酸(N-Methyl-D-aspartic acid,NMDA)受体的磷酸化,TrkB信号可能导致钙和钠内流的增加。故电针治疗脊髓损伤,可使BDNF与TrkB高亲和力结合,促进脊髓损伤的修复。其可能是通过激活BDNF-TrkB信号通路,抑制BDNF前体(brain-derived neurotrophic factor precursor,proBDNF)-p75^(NTR)信号通路来实现对神经的再生修复。

Research progress on the biological effects of BDNF and proBDNFs in post-traumatic stress disorder

Many people were affected psycho-logically and even traumatized by the outbreak of new coronavirus pneumonia in 2020,which has the potential to lead to post-traumatic stress disorder.Many neuropsy-chiatric illnesses are aided by brain-derived neurotrophic factor and its predecessors.Brain-derived neurotrophic factor precursors have the biological impact of triggering neuronal apoptosis and hindering neural regeneration,and brain-derived neurotrophic factor itself can help increase the growth,survival,and differentiation of central and peripheral nerve cells.This article provides an in-depth study of their biological impacts in post-traumatic stress disorder in an attempt to understand the biological effects of brain-derived neurotrophic factor and its precursor proteins.

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 associated with neuronal dysfunction,altered synaptic plasticity,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 synaptic 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.

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.

Enhanced expression of proneurotrophins in elevated introcular pressure-induced rat retinal ischemia

Background Proneurotrophins such as the precursor of nerve growth factor （proNGF） and the precursor of brain-derived neurotrophic factor （proBDNF） interacted with sortilin and p75NTR to form a complex capable of activating an apoptotic signaling. We found that the expression of p75NTR and sortilin was increased in ischemic retina induced by elevated intraocular pressure （lOP）, but the protein expression changes of proNGF and proBDNF in the same situation were not clear. This study aimed to ascertain the protein expression changes of proNGF and proBDNF in ischemic retina induced by elevated lOP.

脑源性神经营养因子前体基因重组蛋白的原核表达和活性鉴定

目的：原核表达脑源性神经营养因子前体（ proBDNF ）基因重组蛋白，并检测其生物学活性。方法通过PCR方法扩增大鼠点突变型基因的脑源性神经营养因子前体的cDNA，克隆到质粒pET-28a中，在大肠杆菌BL21中表达，其表达产物经Western印迹方法鉴别，用DAPI法检测其对PC12细胞凋亡的影响。结果重组基因的扩增产物在大肠杆菌中获得表达，表达产物符合目的蛋白分子量并能够与特异性抗体反应。原核表达的proBDNF基因重组蛋白能够诱导PC12细胞的凋亡。结论成功地在大肠杆菌BL21中表达了proBDNF基因重组蛋白，该蛋白能够对促进PC12细胞的凋亡，具有生物毒性。