Mouse spermatogenesis entails the maintenance and self-renewal of spermatogonial stem cells (SSCs), which require a complex web-like signaling network transduced by various cytokines. Although brain-derived neurotrophic factor (BDNF) is expressed in Sertoli cells in the testis, and its receptor tropomyosin receptor kinase B (TrkB) is expressed in the spermatogonial population containing SSCs, potential functions of BDNF for spermatogenesis have not been uncovered. Here, we generate BDNF conditional knockout mice and find that BDNF is dispensable for in vivo spermatogenesis and fertility. However, in vitro , we reveal that BDNF -deficient germline stem cells (GSCs) exhibit growth potential not only in the absence of glial cell line-derived neurotrophic factor (GDNF), a master regulator for GSC proliferation, but also in the absence of other factors, including epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and insulin. GSCs grown without these factors are prone to differentiation, yet they maintain expression of promyelocytic leukemia zinc finger ( Plzf ), an undifferentiated spermatogonial marker. Inhibition of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Src pathways all interfere with the growth of BDNF-deficient GSCs. Thus, our findings suggest a role for BDNF in maintaining the undifferentiated state of spermatogonia, particularly in situations where there is a shortage of growth factors.
Animals ; Male ; Brain-Derived Neurotrophic Factor/genetics* ; Spermatogonia/cytology* ; Mice ; Spermatogenesis/genetics* ; Mice, Knockout ; Cell Differentiation ; Glial Cell Line-Derived Neurotrophic Factor/genetics* ; Promyelocytic Leukemia Zinc Finger Protein/genetics* ; Cell Survival/physiology* ; Signal Transduction/physiology* ; Cell Proliferation/physiology*

Cardiovascular disease (CVD) poses a serious threat to human health. Exercise plays an important role in both the prevention and treatment of CVD and is one of the key non-pharmacological interventions. Exercise can regulate the level of exerkine secreted by different tissue cells, directly affect the cardiovascular system or play a role in cardiovascular protection by improving cardiovascular risk factors. Exerkine such as meteorin-like protein (Metrnl), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and exosomal microRNA (miRNA) play an important role in regulating vascular and cardiac diseases such as atherosclerosis, heart failure, cardiac ischemia-reperfusion and myocardial infarction, as well as their risk factors. Exploring the signaling pathways and mechanisms by which Metrnl, BDNF, FGF21, and exosomal miRNAs exert cardiovascular protective effects can provide novel insights into exercise-based strategies for preventing and treating cardiovascular diseases.
Humans ; Cardiovascular Diseases/prevention & control* ; Exercise/physiology* ; Fibroblast Growth Factors/physiology* ; MicroRNAs/metabolism* ; Brain-Derived Neurotrophic Factor/physiology* ; Cardiovascular System/physiopathology* ; Exosomes/metabolism* ; Signal Transduction

OBJECTIVES: The neurotoxicity of carbon monoxide (CO) to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Our previous study found that retinoic acid (RA) can suppress the neurotoxic effects of CO. This study further explores, in vivo and in vitro, the molecular mechanisms by which RA alleviates CO-induced central nervous system damage. METHODS: A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO, and a DEACMP animal model was established in adult Kunming mice. Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin V/propidium iodide (PI) double staining. The transcriptional and protein expression of each gene was detected using real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Long noncoding RNA (lncRNA) SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes. In DEACMP mice, SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression. RESULTS: RA at 10 and 20 μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes, downregulation of SNHG15 and LINGO-1, and upregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) (all P<0.05). Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity (all P<0.05). Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels (all P<0.05). Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP (all P<0.05). CONCLUSIONS RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby reducing central nervous system injury and exerting neuroprotective effects. LncRNA SNHG15 and LINGO-1 are key molecules mediating RA-induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway. These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.
Animals ; RNA, Long Noncoding/physiology* ; Brain-Derived Neurotrophic Factor/genetics* ; Carbon Monoxide Poisoning/complications* ; Mice ; Tretinoin/pharmacology* ; Nerve Tissue Proteins/metabolism* ; Membrane Proteins/metabolism* ; Apoptosis/drug effects* ; Hippocampus/cytology* ; Receptor, trkB/metabolism* ; Neurons/drug effects* ; Male ; Brain Diseases/etiology* ; Oligodendroglia/drug effects* ; Signal Transduction ; Cell Line

Exercise-induced analgesia (EIA) refers to the elevation of pain thresholds and reduction in sensitivity to noxious stimuli achieved through exercise training. As a non-pharmacological treatment strategy, exercise therapy has demonstrated positive effects on both acute and chronic pain. Increasing evidence indicates that modulation of glial cell activity is an important mechanism underlying analgesia. Spinal glial cells contribute to the development and maintenance of pathological pain by promoting pain signal transmission through inflammatory responses and synaptic remodeling. Exercise can differentially regulate microglia and astrocyte activity, inhibiting multiple inflammatory signaling pathways, such as P2X4/P2X7 purinergic receptors, brain-derived neurotrophic factor (BDNF)/phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), interleukin (IL)-6/Janus kinase (JAK) 2/signal transducer and activator of transcription 3 (STAT3), p38-mitogen-activated protein kinases (MAPK), and Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), thereby reducing the release of pro-inflammatory cytokines, decreasing inflammatory and nociceptive hypersensitivity, and alleviating pathological pain. This review also summarized the effects of different exercise intensities, durations, and frequencies on glial cell responses in order to provide a theoretical foundation for optimizing exercise-based interventions for pathological pain conditions.
Humans ; Microglia/metabolism* ; Astrocytes/metabolism* ; Exercise/physiology* ; Signal Transduction ; Analgesia/methods* ; Spinal Cord/cytology* ; Exercise Therapy ; Pain Management/methods* ; Animals ; Brain-Derived Neurotrophic Factor/metabolism*

This commentary highlights the recently published study by Jeon and Ha (Environ Health Prev Med 22:27, 2017) examining the effects of exercise intensity and brain-derived neurotrophic factor (BDNF) on memory in adolescents. This 12-week training study elicited increases in BDNF and improvements in working memory during moderate- and high-intensity exercise, which may have been achieved through improved brain tissue oxygenation, nutrient delivery, and BDNF mRNA expression. These improvements highlight the positive neuroendocrinological effects of BDNF and its role as a potential candidate molecule, as a mediator of synaptic plasticity. In this commentary, we aim to highlight the strengths and potential areas of consideration of Jeon and Ha (Environ Health Prev Med 22:27, 2017). We also offer insight into the clinical implications of this study, such as advocating for exercise in healthy children and as adjunctive therapy in pathological states. This study is promising and further highlights the importance of cardiorespiratory exercise in improving physiological health and cognitive functioning in youth through the phenomenon of neuroplasticity.
Adolescent ; Brain-Derived Neurotrophic Factor ; metabolism ; Exercise ; physiology ; Humans ; Memory ; physiology

To investigate the behavioral and biomolecular similarity between neuralgia and depression, a trigeminal neuralgia (TN) mouse model was established by constriction of the infraorbital nerve (CION) to mimic clinical trigeminal neuropathic pain. A mouse learned helplessness (LH) model was developed to investigate inescapable foot-shock-induced psychiatric disorders like depression in humans. Mass spectrometry was used to assess changes in the biomolecules and signaling pathways in the hippocampus from TN or LH mice. TN mice developed not only significant mechanical allodynia but also depressive-like behaviors (mainly behavioral despair) at 2 weeks after CION, similar to LH mice. MS analysis demonstrated common and distinctive protein changes in the hippocampus between groups. Many protein function families (such as cell-to-cell signaling and interaction, and cell assembly and organization,) and signaling pathways (e.g., the Huntington's disease pathway) were involved in chronic neuralgia and depression. Together, these results demonstrated that the LH and TN models both develop depressive-like behaviors, and revealed the involvement of many psychiatric disorder-related biomolecules/pathways in the pathogenesis of TN and LH.
Animals ; Avoidance Learning ; physiology ; Brain-Derived Neurotrophic Factor ; metabolism ; Depression ; etiology ; pathology ; Disease Models, Animal ; Electroshock ; adverse effects ; Functional Laterality ; Helplessness, Learned ; Hindlimb Suspension ; psychology ; Hippocampus ; metabolism ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Orbit ; innervation ; Pain Measurement ; Proteomics ; methods ; Reaction Time ; physiology ; Signal Transduction ; physiology ; Trigeminal Neuralgia ; etiology ; pathology

OBJECTIVETo study the effect of Buyang Huanwu decoction (BYHWD) inducing angiogenesis on the neuroblast migration from the subventricular zone and its mechanisms after focal cerebral ischemia.

METHODThe middle cerebral artery occlusion (MCAO) was performed to mice for 30 minutes to establish the model. The rats were divided into sham group, model group, BYHWD group and endostatin group. BYHWD (20 g x kg(-1), ig) and endostatin (10 μg, sc) were administered 24 h after ischemia once a day for consecutively 14 days. At 14 d after ischemia, the density of micro-vessel and the number of neuroblasts in the ischemia border zone were determined by immunofluorescence staining. The mRNA and protein expression of cell-derived factor-1 (SDF-1) and brain-derived neurotrophic (BDNF) were examined by real-time PCR and Western blot.

RESULTCompared with the model group, BYHWD significantly increased the density of micro-vessel and the number of DCX positive cells in the ischemia border zone (P < 0.01), and significantly increased the SDF-1 and BDNF mRNA and protein expression (P < 0.01). Compared with BYHWD group, endostatin significantly reduced the density of micro-vessel and the number of DCX positive cells in the ischemia border zone (P < 0.01), as well as the SDF-1, BDNF mRNA and protein expression (P < 0.01).

CONCLUSIONBYHWD could promote the neuroblast migration from the subventricular zone via inducing angiogenesis after cerebral ischemia, the mechanism may be correlated with up-regulating the expression of SDF-1 and BDNF.

Angiogenesis Inducing Agents ; pharmacology ; Animals ; Brain Ischemia ; pathology ; physiopathology ; Brain-Derived Neurotrophic Factor ; analysis ; genetics ; Cell Movement ; drug effects ; Cerebral Ventricles ; pathology ; Chemokine CXCL12 ; analysis ; genetics ; Drugs, Chinese Herbal ; pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Neurons ; drug effects ; physiology

Brain-derived neurotrophic factor (BDNF), a small dimeric secretory protein, plays a vital role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF in the hippocampus and amygdala participates in the formation of fear memory. However, little is known about the functional role of BDNF in the anterior cingulate cortex (ACC). To address this question, we examined the mRNA and protein levels of BDNF in the ACC of rats at various time points after fear conditioning, using quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). The results showed that BDNF exhibited a temporally specific increase in both mRNA and protein levels after CS (tone) and US (foot shock) was paired. Such increase did not occur after the animals were exposed to CS or US alone. When BDNF antibody was locally infused into the ACC prior to CS-US pairing, both contextual and auditory fear memories were severely impaired. Taken together, these results suggest that BDNF in the ACC is required for the formation of fear memory.
Animals ; Brain-Derived Neurotrophic Factor ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Fear ; Gyrus Cinguli ; metabolism ; Memory ; physiology ; RNA, Messenger ; metabolism ; Rats ; Real-Time Polymerase Chain Reaction

OBJECTIVETo observe the effect of Draconis Sanguis-containing serum on the expressions of NGF, BDNF, CNTF, LNG-FR, TrkA, GDNF, GAP-43 and NF-H in Schwann cells, and investigate the possible mechanism of Draconis Sanguis to promote peripheral nerve regeneration.

METHODSD rats were randomly divided into 2 groups: the Draconis Sanguis group (orally administered with Draconis Sanguis-containing balm solution) and the blank group (equivoluminal balm) to prepare Draconis Sanguis-containing serum and blank control serum. Schwann cells were extracted from double sciatic nerves of three-day-old SD rats, divided into 2 groups: the Draconis Sanguis group and the blank control group, and respectively cultured with 10% Draconis Sanguis-containing serum or blank control serum. The mRNA expressions of NGF, BDNF, CNTF and other genes in Schwann cells were measured by RT-PCR analysis 48 hours later.

RESULTMost of the Schwann cells were bipolar spindle and arranged shoulder to shoulder or end to end under the microscope and identified to be positive with the immunocytochemical method. To compare with the blank group, mRNA expressions of NGF, LNGFR, GDNF and GAP-43 significantly increased (P < 0.01). Whereas that of BDNF decreased significantly (P < 0.05), and so did that of TrkA, CNTF (P < 0.01), with no remarkable difference in NF-H-mRNA.

CONCLUSIONTraditional Chinese medicine Draconis Sanguis may show effect in nerve regeneration by up-regulating mRNA expressions of NGF, LNGFR, GDNF and GAP-43 and down-regulating mRNA expressions of TrkA, BDNF and CNTF.

Animals ; Arecaceae ; chemistry ; Brain-Derived Neurotrophic Factor ; genetics ; metabolism ; Cells, Cultured ; Ciliary Neurotrophic Factor ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; GAP-43 Protein ; genetics ; metabolism ; Gene Expression ; drug effects ; Glial Cell Line-Derived Neurotrophic Factor ; genetics ; metabolism ; Male ; Nerve Growth Factor ; genetics ; metabolism ; Nerve Regeneration ; drug effects ; Neurofilament Proteins ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, trkA ; genetics ; metabolism ; Schwann Cells ; drug effects ; physiology ; Serum ; chemistry

The aim of the present study was to investigate the effect of precursor brain-derived neurotrophic factor (proBDNF) on survival and neurite outgrowth of cultured rat spiral ganglion neurons (SGNs). Spiral ganglions (SG) were collected from postnatal day 5 Sprague Dawley (SD) rats, then enzymatically digested and suspended. Dissociated SGNs were plated on poly-D-lysine/laminin coated eight-well chamber plates and maintained at 37 °C for 4 h to promote the attachment of the neurons. Cultured SGNs were randomly divided into five groups: control group, BDNF group (BDNF 10 ng/mL), C10 group (proBDNF 10 ng/mL), C50 group (proBDNF 50 ng/mL), and C100 group (proBDNF 100 ng/mL). All groups were incubated in a serum-free medium. 48 h after incubation, SGNs were fixed and stained for βIII tubulin. Immunostaining of the cultured SGNs showed that, compared with the control group, the cellular survival of C50 group and C100 group were significantly reduced (P < 0.001). Furthermore, surviving numbers of the three proBDNF-treated groups were all lower than the BDNF group. In order to assess the effect of proBDNF on cell morphology, SGNs were divided into two categories: SGNs with or without neurites. The results demonstrated that proBDNF significantly increased the proportions of SGNs without neurites in C10, C50 and C100 groups compared with that in control group (P < 0.001). In addition, c-Jun N-terminal kinase (JNK) inhibitor, SP600125 (20 μmol/L) significantly increased the surviving number of SGNs in C50 group. These results suggest that proBDNF reduces the survival rate of cultured SGNs and inhibits the sprouting of neurites. Furthermore, the inhibition of JNK signaling attenuates the effect of proBDNF on SGNs survival.
Animals ; Axons ; physiology ; Brain-Derived Neurotrophic Factor ; pharmacology ; Cell Survival ; Cells, Cultured ; JNK Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; MAP Kinase Signaling System ; Neurites ; physiology ; Neurons ; cytology ; Protein Precursors ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spiral Ganglion ; cytology