Action Of Brain-derived Neurotrophic Factor Research Articles

Effect of sevoflurane on the ATPase activity of hippocampal neurons in a rat model of cerebral ischemia-reperfusion injury via the cAMP-PKA signaling pathway

We aim to investigate the effects of sevoflurane on the ATPase activity of the hippocampal neurons in rats with cerebral ischemia-reperfusion injury (IRI) via the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling pathway. Sixty rats were assigned into the normal, model and sevoflurane groups (n = 20, the latter two groups were established as focal cerebral IRI models). The ATPase activity was detected using an ultramicro Na (+)-K (+)-ATP enzyme kit. Immunohistochemical staining was used to detect the positive protein expression of cAMP and PKA. The hippocampal neurons were assigned to the normal, IRI, IRI + sevoflurane, IRI + forskolin, IRI + H89 and IRI + sevoflurane + H89 groups. qRT-PCR and Western blotting were performed for the expressions of cAMP, PKA, cAMP-responsive element-binding protein (CREB) and brain derived neurotrophic factor (BDNF). The normal and sevoflurane groups exhibited a greater positive protein expression of cAMP and PKA than the model group. Compared with the normal group, the expressions of cAMP, PKA, CREB and BDNF all reduced in the IRI, model and IRI + H89 groups. The sevoflurane group showed higher cAMP, PKA, CREB and BDNF expressions than the model group. Compared with the IRI group, ATPase activity and expressions of cAMP, PKA, CREB and BDNF all increased in the normal, IRI + sevoflurane and IRI + forskolin groups but decreased in the IRI + H89 group. It suggests that sevoflurane could enhance ATPase activity in hippocampal neurons of cerebral IRI rats through activating cAMP-PKA signaling pathway.

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis.

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs.

Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma.

Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity‐ and brain‐derived neurotrophic factor (BDNF)‐dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro‐2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol‐requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x‐box‐binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation‐dependent up‐regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1‐XBP1 pathway in a protein kinase A‐dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A‐IRE1‐XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1‐XBP1 signaling. Synaptic activity‐ and BDNF‐dependent distinct activation of dendritic IRE1‐XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159.

Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect.

Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and plays critical roles in memory and synapse formation, as well as exerting antidepressant-like effects in psychiatric disorders. We previously reported that BDNF is expressed in salivary glands and affects blood BDNF content. However, the function of salivary BDNF remains unclear. The aim of this study was to generate transgenic mice overexpressing BDNF in the salivary glands. Hence, we used the Lama construct (hemagglutinin (HA)-tagged mouse Bdnf cDNA) to specifically express BDNF in mouse salivary glands. Compared with control mice, Bdnf-HA transgenic mice showed increased blood BDNF and expressed salivary BDNF-HA. Molecular analysis revealed enhanced hippocampal BDNF levels and activation of the BDNF receptor, tyrosine kinase B (TrkB), in transgenic mice. In both the open field and elevated-plus maze tests, transgenic mice showed anxiolytic-like behavioral effects compared with control or sialoadenectomized mice. Among downstream components of the BDNF-TrkB signaling pathway, metabolic activation of the γ-aminobutyric acid (GABA) synthetic pathway was found, including higher levels of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1). Thus, we have established a transgenic mouse expressing BDNF in the parotid gland that may be useful to examine the hippocampal effects of salivary BDNF.

Role of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in psychological stress and depression.

Major depressive disorder is a common illness worldwide, but the pathogenesis of the disorder remains incompletely understood. The tissue-type plasminogen activator-plasminogen proteolytic cascade is highly expressed in the brain regions involved in mood regulation and neuroplasticity. Accumulating evidence from animal and human studies suggests that tissue-type plasminogen activator and its chief inhibitor, plasminogen activator inhibitor-1, are related to stress reaction and depression. Furthermore, the neurotrophic hypothesis of depression postulates that compromised neurotrophin brain-derived neurotrophic factor (BDNF) function is directly involved in the pathophysiology of depression. In the brain, the proteolytic cleavage of proBDNF, a BDNF precursor, to mature BDNF through plasmin represents one mechanism that can change the direction of BDNF action. We also discuss the implications of tissue-type plasminogen activator and plasminogen activator inhibitor-1 alterations as biomarkers for major depressive disorder. Using drugs that increase tissue-type plasminogen activator or decrease plasminogen activator inhibitor-1 levels may open new avenues to develop conceptually novel therapeutic strategies for depression treatment.

Is There a Role for Bioactive Lipids in the Pathobiology of Diabetes Mellitus?

Inflammation, decreased levels of circulating endothelial nitric oxide (eNO) and brain-derived neurotrophic factor (BDNF), altered activity of hypothalamic neurotransmitters (including serotonin and vagal tone) and gut hormones, increased concentrations of free radicals, and imbalance in the levels of bioactive lipids and their pro- and anti-inflammatory metabolites have been suggested to play a role in diabetes mellitus (DM). Type 1 diabetes mellitus (type 1 DM) is due to autoimmune destruction of pancreatic β cells because of enhanced production of IL-6 and tumor necrosis factor-α (TNF-α) and other pro-inflammatory cytokines released by immunocytes infiltrating the pancreas in response to unknown exogenous and endogenous toxin(s). On the other hand, type 2 DM is due to increased peripheral insulin resistance secondary to enhanced production of IL-6 and TNF-α in response to high-fat and/or calorie-rich diet (rich in saturated and trans fats). Type 2 DM is also associated with significant alterations in the production and action of hypothalamic neurotransmitters, eNO, BDNF, free radicals, gut hormones, and vagus nerve activity. Thus, type 1 DM is because of excess production of pro-inflammatory cytokines close to β cells, whereas type 2 DM is due to excess of pro-inflammatory cytokines in the systemic circulation. Hence, methods designed to suppress excess production of pro-inflammatory cytokines may form a new approach to prevent both type 1 and type 2 DM. Roux-en-Y gastric bypass and similar surgeries ameliorate type 2 DM, partly by restoring to normal: gut hormones, hypothalamic neurotransmitters, eNO, vagal activity, gut microbiota, bioactive lipids, BDNF production in the gut and hypothalamus, concentrations of cytokines and free radicals that results in resetting glucose-stimulated insulin production by pancreatic β cells. Our recent studies suggested that bioactive lipids, such as arachidonic acid, eicosapentaneoic acid, and docosahexaenoic acid (which are unsaturated fatty acids) and their anti-inflammatory metabolites: lipoxin A4, resolvins, protectins, and maresins, may have antidiabetic actions. These bioactive lipids have anti-inflammatory actions, enhance eNO, BDNF production, restore hypothalamic dysfunction, enhance vagal tone, modulate production and action of ghrelin, leptin and adiponectin, and influence gut microbiota that may explain their antidiabetic action. These pieces of evidence suggest that methods designed to selectively deliver bioactive lipids to pancreatic β cells, gut, liver, and muscle may prevent type 1 and type 2 DM.

Anti-depressant-like effects of Jieyu chufan capsules in a mouse model of unpredictable chronic mild stress.

Jieyu chufan (JYCF) is a well-known Chinese traditional medicine used for depression; however, the molecular mechanism underlying its anti-depressant action has remained elusive. In the present study, the anti-depressant effects of JYCF and the potential mechanisms were investigated in a mouse model. Five groups of 12 C57BL/6 mice each were used in the study, including a normal control group (NC group), a model control group (MC group) and three groups, which received different doses of JYCF (1.25, 2.5 and 5 g/kg) orally for 21 days (JYCF groups). The MC group and the three JYCF groups were subjected to 3 weeks of unpredictable chronic mild stress (UCMS) to induce depression-like behavior. All groups were subjected to a sucrose consumption test along with a forced swimming test to confirm depression-like behavior, an open-field test and an elevated plus maze test to confirm anxiety-like behavior, and a Morris water maze test to evaluate spatial learning and memory. In addition, synaptic density in the hippocampus was evaluated and western blot and immunostaining were used to analyze hippocampal expression of postsynaptic density protein-95 (PSD95), synaptophysin (Syn), cyclic adenosine monophosphate response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), Akt and glycogen synthase kinase (GSK)-3β as well as their phosphorylated (p) versions. The results showed that JYCF (2.5 and 5 g/kg) alleviated depressive-like behaviors and increased synaptic density in UCMS mice. Moreover, JYCF upregulated the expression of PSD95, Syn and BDNF and increased phosphorylated Akt, CREB and GSK-3β in the hippocampus. These results suggested that JYCF exerts an anti-depressant-like activity in UCMS-induced mice, which is likely to be mediated by reversing the stress-induced disruption of BDNF and GSK-3β activity.

Use of Brevibacillus choshinensis for the production of biologically active brain-derived neurotrophic factor (BDNF).

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family critical for neuronal cell survival and differentiation, with therapeutic potential for the treatment of neurological disorders and spinal cord injuries. The production of recombinant, bioactive BDNF is not practical in most traditional microbial expression systems because of the inability of the host to correctly form the characteristic cystine-knot fold of BDNF. Here, we investigated Brevibacillus choshinensis as a suitable expression host for bioactive BDNF expression, evaluating the effects of medium type (2SY and TM), temperature (25 and 30°C), and culture time (48-120h). Maximal BDNF bioactivity (per unit mass) was observed in cultures grown in 2SY medium at extended times (96h at 30°C or >72h at 25°C), with resulting bioactivity comparable to that of a commercially available BDNF. For cultures grown in 2SY medium at 25°C for 72h, the condition that led to the greatest quantity of biologically active protein in the shortest culture time, we recovered 264μg/L of BDNF. As with other microbial expression systems, BDNF aggregates did form in all culture conditions, indicating that while we were able to recover biologically active BDNF, further optimization of the expression system could yield still greater quantities of bioactive protein. This study provides confirmation that B. choshinensis is capable of producing biologically active BDNF and that further optimization of culture conditions could prove valuable in increasing BDNF yields.

BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the “weaver” mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor

Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB).Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the “weaver” mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing “weaver” with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway.These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD.

Neuroprotective Role of Exogenous Brain-Derived Neurotrophic Factor in Hypoxia-Hypoglycemia-Induced Hippocampal Neuron Injury via Regulating Trkb/MiR134 Signaling.

Hypoxic-ischemic brain injury is an important cause of neonatal mortality and morbidity. Brain-derived neurotrophic factor (BDNF) has been reported to play a neuroprotective role in hypoxic-ischemic brain injury; however, the specific effects and mechanism of BDNF on hypoxic-hypoglycemic hippocampal neuron injury remains unknown. The current study investigated the action of BDNF in regulating cerebral hypoxic-ischemic injury by simulating hippocampal neuron ischemia and hypoxia. We found that BDNF, p-Trkb, and miR-134 expression levels decreased, and that exogenous BDNF increased survival and reduced apoptosis in hypoxic-hypoglycemic hippocampal neurons. The results also show that BDNF inhibits MiR-134 expression by activating the TrkB pathway. Transfection with TrkB siRNA and pre-miR-134 abrogated the neuroprotective role of BDNF in hypoxic-hypoglycemic hippocampal neurons. Our results suggest that exogenous BDNF alleviates hypoxic-ischemic brain injury through the Trkb/MiR-134 pathway. These findings may help to identify a potential therapeutic agent for the treatment of hypoxic-ischemic brain injury.

Synapsins regulate brain-derived neurotrophic factor-mediated synaptic potentiation and axon elongation by acting on membrane rafts.

In neurons, intracellular membrane rafts are essential for specific actions of brain-derived neurotrophic factor (BDNF), which include the regulation of axon outgrowth, growth cone turning and synaptic transmission. Virtually, all the actions of BDNF are mediated by binding to its receptor, TrkB. The association of TrkB with the tyrosine kinase, Fyn, is critical for its localization to intracellular membrane rafts. Here, we show that synapsins, a family of highly amphipathic neuronal phosphoproteins, regulate membrane raft lipid composition and consequently, the ability of BDNF to regulate axon/neurite development and potentiate synaptic transmission. In the brains of mice lacking all synapsins, the expression of both BDNF and TrkB were increased, suggesting that BDNF/TrkB-mediated signaling is impaired. Consistent with this finding, synapsin-depleted neurons exhibit altered raft lipid composition, deficient targeting of Fyn to rafts, attenuated TrkB activation, and abrogation of BDNF-stimulated axon outgrowth and synaptic potentiation. Conversely, overexpression of synapsins in neuroblastoma cells results in corresponding reciprocal changes in raft lipid composition, increased localization of Fyn to rafts and promotion of BDNF-stimulated neurite formation. In the presence of synapsins, the ratio of cholesterol to estimated total phospholipids converged to 1, suggesting that synapsins act by regulating the ratio of lipids in intracellular membranes, thereby promoting lipid raft formation. These studies reveal a mechanistic link between BDNF and synapsins, impacting early development and synaptic transmission.

Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus.

Brain-derived neurotrophic factor (BDNF) is an activity-dependent neurotrophin critical for neuronal plasticity in the hippocampus. BDNF is encoded by multiple transcripts with alternative 5' untranslated regions (5'UTRS) that display activity-induced targeting to distinct subcellular compartments. While individual Bdnf 5'UTR transcripts influence dendrite morphology in cultured hippocampal neurons, it is unknown whether Bdnf splice variants impact dendrite arborization in functional classes of neurons in the intact hippocampus. Moreover, the contribution of Bdnf 5'UTR splice variants to dendritic spine density and shape has not been explored. We analyzed the structure of CA1 and CA3 dendrite arbors in transgenic mice lacking BDNF production from exon (Ex) 1, 2, 4, or 6 splice variants (Bdnf-e1, -e2, -e4, and -e6-/- mice) and found that loss of BDNF from individual Bdnf mRNA variants differentially impacts the complexity of apical and basal arbors in vivo. Consistent with the subcellular localization studies, Bdnf Ex2 and Ex6 transcripts significantly contributed to dendrite morphology in both CA1 and CA3 neurons. While Bdnf-e2-/- mice showed increased branching proximal to the soma in CA1 and CA3 apical arbors, Bdnf-e6-/- mice showed decreased apical and basal dendrite complexity. Analysis of spine morphology on Bdnf-e6-/- CA1 dendrites revealed changes in the percentage of differently sized spines on apical, but not basal, branches. These results provide further evidence that Bdnf splice variants generate a spatial code that mediates the local actions of BDNF in distinct dendritic compartments on structural and functional plasticity.

Prolonged maternal separation attenuates BDNF-ERK signaling correlated with spine formation in the hippocampus during early brain development.

Maternal separation (MS) is known to affect hippocampal function such as learning and memory, yet the molecular mechanism remains unknown. We hypothesized that these impairments are attributed to abnormities of neural circuit formation by MS, and focused on brain-derived neurotrophic factor (BDNF) as key factor because BDNF signaling has an essential role in synapse formation during early brain development. Using rat offspring exposed to MS for 6h/day during postnatal days (PD) 2-20, we estimated BDNF signaling in the hippocampus during brain development. Our results show that MS attenuated BDNF expression and activation of extracellular signal-regulated kinase (ERK) around PD 7. Moreover, plasticity-related immediate early genes, which are transcriptionally regulated by BDNF-ERK signaling, were also reduced by MS around PD 7. Interestingly, detailed analysis revealed that MS particularly reduced expression of BDNF gene and immediate early genes in the cornu ammonis 1 (CA1) of hippocampus at PD 7. Considering that BDNF-ERK signaling is involved in spine formation, we next evaluated spine formation in the hippocampus during the weaning period. Our results show that MS particularly reduced mature spine density in proximal apical dendrites of CA1 pyramidal neurons at PD 21. These results suggest that MS could attenuate BDNF-ERK signaling during primary synaptogenesis with a region-specific manner, which is likely to lead to decreased spine formation and maturation observed in the hippocampal CA1 region. It is speculated that this incomplete spine formation during early brain development has an influence on learning capabilities throughout adulthood.

Ceftriaxone attenuates glutamate-mediated neuro-inflammation and restores BDNF in MPTP model of Parkinson’s disease in rats

The present study is designed to investigate the role of glutamate transporter in neuroprotection of ceftriaxone against MPTP induced PD animal model. Young male Wistar rats were subjected to intra-nigral administration of MPTP for the induction of Parkinson’s disease. Glutamate modulators like ceftriaxone (CFX), Memantine (MEM) and Dihydrokainate (DHK) were administered to MPTP-lesioned rats. Different behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and different biochemical parameters were measured. Intranigral administration of MPTP showed significant impairment of motor behavior and marked increase in inflammatory mediators and oxidative stress parameters in rats. In addition, MPTP also produced significant decrease in brain-derived neurotrophic factor (BDNF) in striatum of rats. However, chronic administration of ceftriaxone (200mg/kg) has shown significant improvement in motor behavioral deficits and oxidative damage. In addition, Ceftriaxone also attenuated the marked increase of NFκB, TNF-α and IL-1β in MPTP treated rats thus, conferring its neuro-inflammatory property. Further, Ceftriaxone significantly restored the decreased activity of BDNF in striatum of MPTP treated rats. Moreover, pre-treatment of memantine (20mg/kg) with sub-therapeutic dose of ceftriaxone (100mg/kg) potentiated the protective effect of ceftriaxone. Furthermore, intra-nigral injection of DHK (200 nmol) with lower dose of ceftriaxone (100mg/kg) reversed the protective effect of ceftriaxone in MPTP treated rats. The present study concluded that ceftriaxone produce beneficial effect against MPTP induced PD like symptoms rats through glutamatergic pathways.

Changes in fMRI activation in anterior hippocampus and motor cortex during memory retrieval after an intense exercise intervention

Strong evidence indicates that regular aerobic training induces beneficial effects on cognitive functions. The present controlled fMRI study was designed to investigate the impact of a short-term intense aerobic exercise on the pattern of functional activation during the retrieval of learned pair-associates in 17 young and healthy male adults compared to 17 matched control subjects. We further aimed to relate putative changes in hippocampal activation to postulated changes in the exercised-induced brain derived neurotrophic factor (BDNF). The supervised exercise program was performed on a bicycle ergometer and lasted six weeks, with three aerobic sessions per week.We found profound improvement of physical fitness in most subjects indicated by the target parameter ‘individual anaerobic threshold’. Significant improvements in the cognitive performance were detected in the exercise group, but also in the control group. We observed significant differences in the activation pattern of the left anterior hippocampus during the pair-associates task after the intervention. We could also show a significant positive correlation between changes in exercise-induced BDNF and left anterior hippocampal activation. Moreover, we observed the brain’s motor network to be significantly stronger activated after the exercise intervention. Thus, our results suggest BDNF dependent activation changes of the hippocampus in addition to previously described structural changes after exercise.

BDNF Propeptide: A Novel Modulator of Synaptic Plasticity.

One of the most characterized neurotrophic factors is brain-derived neurotrophic factor (BDNF), which regulates neuronal survival and differentiation, and functions in activity-dependent plasticity processes such as long-term potentiation, long-term depression (LTD), and learning memory. Similar to other growth factors, BDNF protein is produced by transcriptional and translational mechanisms. Nevertheless, a posttranslational mechanism, the proteolytic conversion of precursor BDNF into at least two fragments, bioactive BDNF and the prodomain, has not been well elucidated. Recently, we demonstrated that the BDNF prodomain, which is named the BDNF propeptide, was endogenously secreted from neuronal cells and facilitated a cellular mechanism of LTD, suggesting the manner through which this posttranslational mechanism multiplies the biological actions of BDNF. In this chapter, we focus on the BDNF propeptide, especially in synaptic plasticity, and discuss the role of this molecule in the brain. The findings regarding the BDNF propeptide would provide new insights for understanding the mechanisms of action of the propeptides of growth factors as well as the biological roles of neurotrophins.

Brain-derived neurotrophic factor (BDNF) and oxidative stress in heroin-dependent male patients undergoing methadone maintenance treatment

Brain-derived neurotrophic factor (BDNF) and oxidative stress may play a role in patients with heroin dependence. The aim of this study was to investigate the serum levels and activities of BDNF and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), and 8-hydroxy 2'-deoxyguanosine (8-OHdG), in heroin-dependent patients undergoing methadone maintenance treatment (MMT). 60 heroin-dependent male MMT patients and 30 healthy males were recruited for this study. The serum BDNF and oxidative stress markers of these subjects were measured with assay kits. Analyses of covariance (ANCOVAs) with age and body mass index adjustments indicated that the serum levels of BDNF in the MMT patients were significantly higher than those in the healthy controls (F=5.169; p=0.026). However, there were no significant differences between the heroin-dependent patients and the healthy controls in the serum levels or activities of oxidative stress markers (p>0.05). In conclusion, our results suggest that MMT increases BDNF levels in heroin-dependent patients, and that patients undergoing MMT might be in a balanced state of reduced oxidation.

Zinc Interactions With Brain-Derived Neurotrophic Factor and Related Peptide Fragments.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal development and survival, synaptic plasticity, and cognitive function. Dysregulation of BDNF signaling is involved in several neurodegenerative disorders, including Alzheimer's disease. Alteration of metal ion homeostasis is observed both in normal aging and in many neurodegenerative diseases. Interestingly, there is a significant overlap between brain areas characterized by metal ion dyshomeostasis and those where BDNF exerts its biological activity. Therefore, it is reasonable to speculate that metal ions, especially zinc, can modulate the activity of BDNF. The synthesis of BDNF peptidomimetic can be helpful both to understand the molecular interaction of BDNF with metal ions and to develop new drugs for neurodegenerative diseases.

Sex differences in brain-derived neurotrophic factor signaling and functions.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that plays a critical role in numerous neuronal activities. Recent studies have indicated that some functions or action mechanisms of BDNF vary in a sex-dependent manner. In particular, BDNF content in some brain parts and the tendency to develop BDNF deficiency-related diseases such as depression are greater in female animals. With the support of relevant studies, it has been suggested that sex hormones or steroids can modulate the activities of BDNF, which may account for its functional discrepancy in different sexes. Indeed, the cross-talk between BDNF and sex steroids has been detected for decades, and some sex steroids, such as estrogen, have a positive regulatory effect on BDNF expression and signaling. Thus, the sex of animal models that are used in studying the functions of BDNF is critical. This Mini-Review summarizes our current findings on the differences in expression, signaling, and functions of BDNF between sexes. We also discuss the potential mechanisms for mediating these differential responses, with a specific emphasis on sex steroids. By presenting and discussing these findings, we seek to encourage researchers to take sex influences into consideration when designing experiments, interpreting results, and drawing conclusions. © 2016 Wiley Periodicals, Inc.

PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma.

Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells. A tumor xenograft model using SCID-Beige mice was utilized to detect the metastasis of NB tumors in vivo. Inhibitors of PI3K, MAPK, Akt, and mTOR were used. Western blotting was performed to study the expressions of P-Akt, P-Erk, and P-mTOR. Our results showed that in TrkB-expressing NB cells, BDNF treatment significantly increased gap closing (P < 0.01) in scratch wound healing assay, also significantly enhanced the numbers of migrating cells (P < 0.01) and invading cells (P < 0.01) in the Boyden chamber migration and invasion assays. In vivo, NB distant metastases were significantly increased in mice with TrkB-expressing xenograft tumors compared to those with non-TrkB-expressing tumors (P < 0.05). Pre-treatment with any of the inhibitors for PI3K (LY294002), MAPK (PD98059), Akt (perifosine), or mTOR (rapamycin) blocked the BDNF/TrkB-induced increases of cell migration and invasion in TB3 cells, and also blocked the BDNF/TrkB-induced expressions of P-Akt, P-Erk, and P-mTOR. These data indicated that BDNF/TrkB increased metastasis in NB via PI3K/Akt/mTOR and MAPK pathways, and BDNF/TrkB and the downstream targets may be potential targets for the treatment of NB metastasis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5433-z) contains supplementary material, which is available to authorized users.