Retraction Note to: MicroRNA-322 Cluster Promotes Tau Phosphorylation via Targeting Brain-Derived Neurotrophic Factor

Neurochemical Research - The Editors have retracted this article [1] following an investigation conducted by the journal. After publication concerns were raised regarding interpretation of the data...     

Brain-Derived Neurotrophic Factor from Bone Marrow-Derived Cells Promotes Post-Injury Repair of Peripheral Nerve

Brain-derived neurotrophic factor (BDNF) stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs) in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/−) received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT) were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI), and motor nerve conduction velocity (MNCV) simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/− mice showed a loss of function with delayed histological recovery and BDNF+/+→BDNF+/− BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/− mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair.     

Brain-Derived Neurotrophic Factor in Post-Partum Depressive Mothers

Postpartum depression (PPD) is the most common psychiatric complication observed in women after they give birth. Some women are particularly sensitive to hormonal changes, starting in early menarche, thus increasing their vulnerability to psychological stressing agents that are triggered by environmental and physiological factors throughout their lives. Decreased serum brain-derived neurotrophic factor (BDNF) levels have been associated to different neuropsychiatric conditions and BDNF has been considered as a candidate marker for such dysfunctions. The goal of this study was to compare the levels of BDNF between mothers who suffer from PPD and healthy control mothers as well as to searching for associations between BDNF levels and the severity of PPD. This is a case-control study including 36 mothers with PPD and 36 healthy control mothers. PPD was defined according to the Beck Depression Inventory (BDI). Serum BDNF was assayed with the sandwich ELISA method. Results: Serum levels of BDNF were significantly lower in women with PPD than in control mothers (P?≤?0.03). A significant negative correlation between BDI score and serum BDNF levels was observed (P?≤?0.02 and r?=?-0.29). Our study demonstrated that low BDNF levels are associated with PPD. This result point out to the potential usage of BDNF in the screening of PPD, which could promote early treatment and, therefore, reduce the burden to the PPD women and to the health system.     

Hemodialysis Decreases Serum Brain-Derived Neurotrophic Factor Concentration in Humans

In the present study we have evaluated the effect of a single hemodialysis session on the brain-derived neurotrophic factor levels in plasma [BDNF]_pl and in serum [BDNF]_s as well as on the plasma isoprostanes concentration [F₂ isoprostanes]_pl, plasma total antioxidant capacity (TAC) and plasma cortisol levels in chronic kidney disease patients. Twenty male patients (age 69.8?±?2.9?years (mean?±?SE)) with end-stage renal disease undergoing maintenance hemodialysis on regular dialysis treatment for 15?C71?months participated in this study. A single hemodialysis session, lasting 4.2?±?0.1?h, resulted in a decrease (P?=?0.014) in [BDNF]_s by ~42?% (2,574?±?322 vs. 1,492?±?327?pg?ml^?1). This was accompanied by an increase (P?<?10^?4) of [F₂-Isoprostanes]_pl (38?±?3 vs. 116?±?16?pg?ml^?1), decrease (P?<?10^?4) in TAC (1,483?±?41 vs. 983?±?35 trolox equivalents, ??mol?l^?1) and a decrease (P?=?0.004) in plasma cortisol level (449.5?±?101.2 vs. 315.3?±?196.3?nmol?l^?1). No changes (P?>?0.05) in [BDNF]_pl and the platelets count were observed after a single dialysis session. Furthermore, basal [BDNF]_s in the chronic kidney disease patients was significantly lower (P?=?0.03) when compared to the age-matched control group (n?=?23). We have concluded that the observed decrease in serum BDNF level after hemodialysis accompanied by elevated [F₂-Isoprostanes]_pl and decreased plasma TAC might be caused by enhanced oxidative stress induced by hemodialysis.     

Explore the Features of Brain-Derived Neurotrophic Factor in Mood Disorders

Objectives

Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal survival and differentiation; however, the effects of BDNF on mood disorders remain unclear. We investigated BDNF from the perspective of various aspects of systems biology, including its molecular evolution, genomic studies, protein functions, and pathway analysis.

Methods

We conducted analyses examining sequences, multiple alignments, phylogenetic trees and positive selection across 12 species and several human populations. We summarized the results of previous genomic and functional studies of pro-BDNF and mature-BDNF (m-BDNF) found in a literature review. We identified proteins that interact with BDNF and performed pathway-based analysis using large genome-wide association (GWA) datasets obtained for mood disorders.

Results

BDNF is encoded by a highly conserved gene. The chordate BDNF genes exhibit an average of 75% identity with the human gene, while vertebrate orthologues are 85.9%-100% identical to human BDNF. No signs of recent positive selection were found. Associations between BDNF and mood disorders were not significant in most of the genomic studies (e.g., linkage, association, gene expression, GWA), while relationships between serum/plasma BDNF level and mood disorders were consistently reported. Pro-BDNF is important in the response to stress; the literature review suggests the necessity of studying both pro- and m-BDNF with regard to mood disorders. In addition to conventional pathway analysis, we further considered proteins that interact with BDNF (I-Genes) and identified several biological pathways involved with BDNF or I-Genes to be significantly associated with mood disorders.

Conclusions

Systematically examining the features and biological pathways of BDNF may provide opportunities to deepen our understanding of the mechanisms underlying mood disorders.     

The Effect of Brain-Derived Neurotrophic Factor on Periodontal Furcation Defects

This study aimed to observe the regenerative effect of brain-derived neurotrophic factor (BDNF) in a non-human primate furcation defect model. Class II furcation defects were created in the first and second molars of 8 non-human primates to simulate a clinical situation. The defect was filled with either, Group A: BDNF (500 µg/ml) in high-molecular weight-hyaluronic acid (HMW-HA), Group B: BDNF (50 µg/ml) in HMW-HA, Group C: HMW-HA acid only, Group D: empty defect, or Group E: BDNF (500 µg/ml) in saline. The healing status for all groups was observed at different time-points with micro computed tomography. The animals were euthanized after 11 weeks, and the tooth-bone specimens were subjected to histologic processing. The results showed that all groups seemed to successfully regenerate the alveolar buccal bone, however, only Group A regenerated the entire periodontal tissue, i.e., alveolar bone, cementum and periodontal ligament. It is suggested that the use of BDNF in combination with a scaffold such as the hyaluronic acid in periodontal furcation defects may be an effective treatment option.     

GMF-Knockout Mice are Unable to Induce Brain-Derived Neurotrophic Factor after Exercise

We earlier reported that overexpression of glia maturation factor (GMF) in cultured astrocytes enhances the production of brain-derived neurotrophic factor (BDNF). The current study was conducted to find out whether BDNF production is impaired in animals devoid of GMF. To this end GMF-knockout (KO) mice were subjected to exercise and the neurotrophin mRNAs were determined by real-time RT-PCR. Compared to wild-type (WT) mice, there is a decrease in exercise-induced BDNF in the KO mice. The observation was correlated with the finding that, in WT mice, exercise increases GMF expression. The results are consistent with the hypothesis that GMF is necessary for exercise-induction of BDNF, and that GMF may promote neuroprotection through BDNF production.     

表达分泌型脑源性神经营养因子的腺相关病毒载体的构建及其表达的检测

采用PCR和体外连接的方法构建了带有信号肽的脑源性神经营养因子(BDNF)的融合基因, 将此基因插入到腺相关病毒载体穿梭质粒pSNAV, 然后用重组质粒pSNAV-Ig-BDNF转染包装细胞, 筛选出永久细胞株后, 用携带腺相关病毒rep及cap基因的单纯疱疹病毒超感染包装细胞, 成功包装出含有目的基因的一型血清型腺相关病毒。经PCR鉴定该病毒含有目的基因片段, 被该病毒感染的细胞裂解液经Western blotting 证实有BDNF表达, 其培养液经ELISA检测证实含有高水平的BDNF蛋白。该病毒与小量的非复制型腺病毒Ad-null联合应用时, 其BDNF蛋白的表达水平显著提高。可弥补腺相关病毒起效慢、对细胞转导效率低的弱点, 为今后应用AAV作基因治疗提供了实验证据。     

表达分泌型脑源性神经营养因子的腺相关病毒载体的构建及其表达的检测

采用PCR和体外连接的方法构建了带有信号肽的脑源性神经营养因子(BDNF)的融合基因, 将此基因插入到腺相关病毒载体穿梭质粒pSNAV, 然后用重组质粒pSNAV-Ig-BDNF转染包装细胞, 筛选出永久细胞株后, 用携带腺相关病毒rep及cap基因的单纯疱疹病毒超感染包装细胞, 成功包装出含有目的基因的一型血清型腺相关病毒。经PCR鉴定该病毒含有目的基因片段, 被该病毒感染的细胞裂解液经Western blotting 证实有BDNF表达, 其培养液经ELISA检测证实含有高水平的BDNF蛋白。该病毒与小量的非复制型腺病毒Ad-null联合应用时, 其BDNF蛋白的表达水平显著提高。可弥补腺相关病毒起效慢、对细胞转导效率低的弱点, 为今后应用AAV作基因治疗提供了实验证据。     

Brain-Derived Neurotrophic Factor Levels in Women with Postpartum Affective Disorder and Suicidality

Our aim was to investigate serum brain-derived neurotrophic factor (BDNF) levels in postpartum women, according to the presence of postpartum affective disorder (PPAD) and suicidality. A cross-sectional study was carried out with women between 45 and 90?days after delivery. PPAD (depression, manic and mixed episode) and suicide risk were assessed using the Mini International Neuropsychiatric Interview. BDNF was assessed using a commercial ELISA kit. Linear regression was used for multivariate analyses. A hundred ninety women participated in the study, 15.3?% had PPAD, 7.4?% showed PPAD with suicide risk. BDNF levels were lower in subjects with three or more Stressful Life Events (P?=?0.01). The serum BDNF levels of women with PPAD presenting suicide risk were significantly lower than those of women without suicide risk (1.50?±?1.38 and 2.33?±?1.28?ng/ml, P?=?0.02). Clinicians should enquire postpartum women about their history of stressful life events, PPAD, and suicidality. This study shows the potential role of BDNF in the neurobiology of the association of PPAD and suicidality.     

Brain-Derived Neurotrophic Factor Inhibits Phenylalanine-Induced Neuronal Apoptosis by Preventing RhoA Pathway Activation

Phenylketonuria (PKU) is neuropathologically characterized by neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction. The neuropathological effect may be due to the ‘toxicity’ of the high concentration of phenylalanine, while little is known about the related treatments to block this effect. In this study, we reported that brain-derived growth factor (BDNF) protected neurons from phenylalanine-induced apoptosis and inhibition of Trk receptor by K252a or downregulation of TrkB abrogated the effect of BDNF. We further demonstrated that phenylalanine-induced RhoA activation and myosin light chain phosphorylation were inhibited by pretreatment with BDNF, while phenylalanine activates the mitochondria-mediated apoptosis through the RhoA/Rho-associated kinase pathway. Thus our studies indicate that the protective effect of BDNF against phenylalanine-induced neuronal apoptosis is probably mediated by suppression of RhoA signaling pathway via TrkB receptor. Taken together, these findings suggest a potential neuroprotective action of BDNF in prevention and treatment of PKU brain injury.     

Rapid Phosphorylation of Phospholipase Cγ 1 by Brain-Derived Neurotrophic Factor and Neurotrophin-3 in Cultures of Embryonic Rat Cortical Neurons

Abstract: Phospholipase Cγ1 (PLC-γ1) is involved at an early step in signal transduction of many hormones and growth factors and catalyzes the hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate to diacylglycerol and inositol trisphosphate, two potent intracellular second messenger molecules. The transformation of PC12 cells into neuron-like cells induced by nerve growth factor is preceded by a rapid stimulation of PLC-γ1 phosphorylation and PI hydrolysis. The present study analyzed the effects of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) on phosphorylation of PLC-γ1 in primary cultures of embryonic rat brain cells. BDNF and NT-3 stimulated the phosphorylation of PLC-γ1, followed by hydrolysis of PI. The stimulation of PLC-γ1 phosphorylation occurred within 20 s after addition of BDNF or NT-3 and lasted up to 30 min, with a peak after 4 min. ED₅₀ values were similar for BDNF and NT-3, with τ25 ng/ml. Phosphorylation of PLC-γ1 by BDNF and NT-3 was found in cultures from all major brain areas. K-252b, a compound known to inhibit selectively neurotrophin actions by interfering with the phosphorylation of trk -type neurotrophin receptors, prevented the BDNF- and NT-3-stimulated phosphorylation of PLC-γ1. Receptors of the trk type were coprecipitated with anti-PLC-γ1 antibodies. The presence of trkB mRNA in the cultures was substantiated by northern blot analysis. The action of BDNF and NT-3 seems to be neuron specific because no phosphorylation of PLC-γ1 was observed in cultures of nonneuronal brain cells. The results provide evidence that developing neurons of the cerebral cortex and other brain areas are responsive to BDNF and NT-3, and they indicate that the transduction mechanism of BDNF and NT-3 in the brain involves rapid phosphorylation of PLC-γ1 followed by PI hydrolysis.     

Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor and Cognitive Function in Non-Demented Subjects

Background

Brain-derived neurotrophic factor (BDNF) is an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity, especially in the hippocampus. We tested hypothesis that reduced CSF BDNF is associated with age-related cognitive decline.

Methodology/Principal Findings, and Conclusions/Significance

CSF concentration of BDNF, Aβ₄₂ and total tau were measured in 128 cognitively normal adults (Normals), 21 patients with Alzheimer''s disease (AD), and nine patients with Mild Cognitive Impairment. Apolipoprotein E and BDNF SNP rs6265 genotype were determined. Neuropsychological tests were performed at baseline for all subjects and at follow-up visits in 50 Normals. CSF BDNF level was lower in AD patients compared to age-matched Normals (p = 0.02). CSF BDNF concentration decreased with age among Normals and was higher in women than men (both p<0.001). After adjusting for age, gender, education, CSF Aβ₄₂ and total tau, and APOE and BDNF genotypes, lower CSF BDNF concentration was associated poorer immediate and delayed recall at baseline (both p<0.05) and in follow up of approximately 3 years duration (both p<0.01).

Conclusions/Significance

Reduced CSF BDNF was associated with age-related cognitive decline, suggesting a potential mechanism that may contribute in part to cognitive decline in older individuals.     

Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM.     

Regulation of Brain-Derived Neurotrophic Factor (BDNF) and Cerebral Dopamine Neurotrophic Factor (CDNF) by Anti-Parkinsonian Drug Therapy In Vivo

Available treatment for Parkinson’s disease (PD) is mainly symptomatic instead of halting or reversing degenerative processes affecting the disease. Research on the molecular pathogenesis of PD has suggested reduced trophic support as a possible cause or mediator of neurodegeneration. In animal models of the disease, neurotrophic factors prevent neurodegeneration and induce behavioral recovery. Some anti-Parkinsonian drugs show neuroprotective activity, but it is not known whether the drug-induced neuroprotection is mediated by neurotrophic factors. In this study, we have investigated the influence of two neuroprotective anti-Parkinsonian drugs, the monoamine oxidase B inhibitor selegiline and the adenosine A_2A antagonist SCH 58261, on the levels of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) in the mouse brain. Protein levels of BDNF and CDNF were quantified by western blot after 2 weeks of treatment with either of the drugs or placebo. CDNF levels were not significantly influenced by selegiline or SCH 58261 in any brain area studied. Selegiline treatment significantly increased BDNF levels in the anterior cingulate cortex (1.55 ± 0.22, P < 0.05, Student’s t-test). In the striatum, selegiline increased BDNF content by 32%, but this change did not reach statistical significance (1.32 ± 0.15, P < 0.13, Student’s t-test). Our data suggest that neurotrophic factors, particularly BDNF may play a role in the neuroprotective effects of selegiline, but do not support the hypothesis that anti-Parkinsonian drugs would work by increasing the levels of CDNF in brain.