Induction Of Brain-derived Neurotrophic Factor Research Articles

Mechanisms of the Beneficial Effects of Exercise on Brain-Derived Neurotrophic Factor Expression in Alzheimer's Disease.

Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer's disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in the AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on the mechanisms behind exercise-induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer's disease pathology. Exercise releases into the circulation a host of hormones and factors from a variety of peripheral tissues. Mechanisms of BDNF induction discussed here are osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are not yet fully understood but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

Dopaminergic neuroprotective effects of inosine in MPTP-induced parkinsonian mice via brain-derived neurotrophic factor upregulation

Parkinson's disease (PD) is the second most common neurodegenerative disease. However, no curative or modifying therapy is known. Inosine is a purine nucleoside that increases brain-derived neurotrophic factor (BDNF) expression in the brain through adenosine receptors. Herein, we investigated the neuroprotective effects of inosine and elucidated the mechanisms underlying its pharmacological action. Inosine rescued SH-SY5Y neuroblastoma cells from MPP+ injury in a dose-dependent manner. Inosine protection correlated with BDNF expression and the activation of its downstream signaling cascade, as the TrkB receptor inhibitor, K252a and siRNA against the BDNF gene remarkably reduced the protective effects of inosine. Blocking the A1 or A2A adenosine receptors diminished BDNF induction and the rescuing effect of inosine, indicating a critical role of adenosine A1 and A2A receptors in inosine-related BDNF elevation. We assessed whether the compound could protect dopaminergic neurons from MPTP-induced neuronal injury. Beam-walking and challenge beam tests revealed that inosine pretreatment for 3 weeks reduced the MPTP-induced motor function impairment. Inosine ameliorated dopaminergic neuronal loss and MPTP-mediated astrocytic and microglial activation in the substantia nigra and striatum. Inosine ameliorated the depletion of striatal dopamine and its metabolite following MPTP injection. BDNF upregulation and the activation of its downstream signaling pathway seemingly correlate with the neuroprotective effects of inosine. To our knowledge, this is the first study to demonstrate the neuroprotective effects of inosine against MPTP neurotoxicity via BDNF upregulation. These findings highlight the therapeutic potential of inosine in dopaminergic neurodegeneration in PD brains.

A systematic analysis of neurobiological roles of lithium

Lithium salts have been the mainstay of treatment for bipolar disorder for more than 50 years, since the FDA approved the treatment in 1970. Molecular mechanisms of lithium's action include inhibition of glycogen synthase kinase 3 beta and inositol monophosphatase, resulting in induction of brain-derived neurotrophic factor, antiapoptotic proteins, deprivation of calcium-induced apoptosis. Recent findings suggest autophagy regulation as a possible mechanism of lithium neuroprotective action. Moreover, lithium treatment has been reported to decrease accumulation of various pathological proteins including phosphorylated tau and amyloid-B. Also, telomeres length and telomerase activity are suggested to be upregulated by lithium. Clinical applications of lithium treatment include various neurodegenerative diseases, primarily Alzheimer disease, with increasing importance given to the use of lithium microdoses. Chemoreactome screening is used to find more safe and effective lithium compounds.

Adipose PTEN acts as a downstream mediator of a brain-fat axis in environmental enrichment

Background/ObjectivesEnvironmental enrichment (EE) is a physiological model to investigate brain-fat interactions. We previously discovered that EE activates the hypothalamic-sympathoneural adipocyte (HSA) axis via induction of brain-derived neurotrophic factor (BDNF), thus leading to sympathetic stimulation of white adipose tissue (WAT) and an anti-obesity phenotype. Here, we investigate whether PTEN acts as a downstream mediator of the HSA axis in the EE. MethodsMice were housed in EE for 4- and 16-week periods to determine how EE regulates adipose PTEN. Hypothalamic injections of adeno-associated viral (AAV) vectors expressing BDNF and a dominant negative form of its receptor were performed to assess the role of the HSA axis in adipose PTEN upregulation. A β-blocker, propranolol, and a denervation agent, 6-hydroydopamine, were administered to assess sympathetic signaling in the observed EE-PTEN phenotype. To determine whether inducing PTEN is sufficient to reproduce certain EE adipose remodeling, we overexpressed PTEN in WAT using an AAV vector. To determine whether adipose PTEN is necessary for the EE-mediated reduction in adipocyte size, we injected a rAAV vector expressing Cre recombinase to the WAT of adult PTENflox mice and placed the mice in EE. ResultsEE upregulated adipose PTEN expression, which was associated with suppression of AKT and ERK phosphorylation, increased hormone-sensitive lipase (HSL) phosphorylation, and reduced adiposity. PTEN regulation was found to be controlled by the HSA axis—with the hypothalamic BDNF acting as the upstream mediator—and dependent on sympathetic innervation. AAV-mediated adipose PTEN overexpression recapitulated EE-mediated adipose changes including suppression of AKT and ERK phosphorylation, increased HSL phosphorylation, and reduced adipose mass, whereas PTEN knockdown blocked the EE-induced reduction of adipocyte size. ConclusionsThese data suggest that adipose PTEN responds to environmental stimuli and serves as downstream mediator of WAT remodeling in the EE paradigm, resulting in decreased adipose mass and decreased adipocyte size.

Effects of exposure to enriched environment during adolescence on passive avoidance memory, nociception, and prefrontal BDNF level in adult male and female rats

Previous studies demonstrated that an enriched environment (EE) exposure improves cognitive functions, synaptic plasticity, neurogenesis, and induction of brain-derived neurotrophic factor (BDNF) in multiple brain regions of laboratory animal models. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. Therefore, the present experiment was aimed to assess the effects of EE during adolescence on passive avoidance learning and memory, nociception, and prefrontal cortex (PFC) BDNF mRNA levels in the adult male and female rats. Our results indicated that housing in the EE during adolescence improves passive avoidance memory and increases nociceptive response against thermal stimulus in both sexes. Findings of our study also showed an increased BDNF level in the PFC of female animals. As a result, sex differences can affect the expression of BDNF mRNA in the PFC. Further research concerning the precise mechanisms underlying sex hormone-dependent production of BDNF in PFC is critical.

Citrus Auraptene Induces Expression of Brain-Derived Neurotrophic Factor in Neuro2a Cells.

(1) Background: Our published data have indicated that (1) auraptene (AUR), a citrus ingredient, has neuroprotective effects on the mouse brain, owing to its ability to suppress inflammation, such as causing a reduction in hyperactivation of microglia and astrocytes; (2) AUR has the ability to trigger phosphorylation (activation) of extracellular signal-related kinase (ERK) and cAMP response element-binding protein (CREB) in neuronal cells; (3) AUR has the ability to induce glial cell line-derived neurotrophic factor (GDNF) synthesis/secretion in rat C6 glioma cells. The well-established fact that the ERK-CREB pathway plays an important role in the production of neurotrophic factors, including GDNF and brain-derived neurotrophic factor (BDNF), prompted us to investigate whether AUR would also have the ability to induce BDNF expression in neuronal cells. (2) Methods: Mouse neuroblastoma neuro2a cells were cultured and the effects of AUR on BDNF mRNA expression and protein content were evaluated by RT-PCR and ELISA, respectively. (3) Results: The levels of BDNF mRNA and secreted BDNF were significantly increased by AUR in a dose- and time-dependent manner in neuro2a cells. (4) Conclusion: The induction of BDNF in neuronal cells might be, in part, one of the mechanisms accounting for the neuroprotective effects of AUR.

Identifying inducers of BDNF gene expression from pharmacologically validated compounds; antipyretic drug dipyrone increases BDNF mRNA in neurons

Low levels of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, are associated with neurological diseases, including depression and Alzheimer’s disease. Therefore, BDNF is a drug target for these diseases. Here we screened for inducers of neuronal Bdnf expression from a pharmacologically validated compound library using our recently developed screening assay based on luciferase activity in cultured cortical neurons. We identified 18 pharmacologically validated compounds, most of which were inferred to induce Bdnf expression by their validated pharmacological actions, such as Gs-coupled receptor activation or neuronal excitation. Unexpectedly, the screening assay identified the antipyretic drug, dipyrone, to increase Bdnf expression. Dipyrone induced endogenous Bdnf expression by Ca2+ influx evoked via L-type voltage-dependent Ca2+ channels and the N-methyl-d-aspartate receptor, indicating that dipyrone induced activity-regulated Bdnf expression in neurons. However, dipyrone-induced Bdnf expression is independent of validated pharmacological effects. Although our screening assay is difficult to reveal how active compounds induce Bdnf expression, this method is convenient to identify inducers of Bdnf expression in primary neurons. Our screening assay evaluated neuronal BDNF induction and can be used to screen for drug re-positioning, as well as novel candidate drugs, for neurological diseases that have low levels of BDNF in the brain.

Neurotrophic interactions between neurons and astrocytes following AAV1-Rheb(S16H) transduction in the hippocampus in vivo.

Background and PurposeWe recently reported that AAV1‐Rheb(S16H) transduction could protect hippocampal neurons through the induction of brain‐derived neurotrophic factor (BDNF) in the rat hippocampus in vivo. It is still unclear how neuronal BDNF produced by AAV1‐Rheb(S16H) transduction induces neuroprotective effects in the hippocampus and whether its up‐regulation contributes to the enhance of a neuroprotective system in the adult brain.Experimental ApproachTo determine the presence of a neuroprotective system in the hippocampus of patients with Alzheimer's disease (AD), we examined the levels of glial fibrillary acidic protein, BDNF and ciliary neurotrophic factor (CNTF) and their receptors, tropomyocin receptor kinase B (TrkB) and CNTF receptor α(CNTFRα), in the hippocampus of AD patients. We also determined whether AAV1‐Rheb(S16H) transduction stimulates astroglial activation and whether reactive astrocytes contribute to neuroprotection in models of hippocampal neurotoxicity in vivo and in vitro.Key ResultsAD patients may have a potential neuroprotective system, demonstrated by increased levels of full‐length TrkB and CNTFRα in the hippocampus. Further AAV1‐Rheb(S16H) transduction induced sustained increases in the levels of full‐length TrkB and CNTFRα in reactive astrocytes and hippocampal neurons. Moreover, neuronal BDNF produced by Rheb(S16H) transduction of hippocampal neurons induced reactive astrocytes, resulting in CNTF production through the activation of astrocytic TrkB and the up‐regulation of neuronal BDNF and astrocytic CNTF which had synergistic effects on the survival of hippocampal neurons in vivo.Conclusions and ImplicationsThe results demonstrated that Rheb(S16H) transduction of hippocampal neurons could strengthen the neuroprotective system and this intensified system may have a therapeutic value against neurodegeneration in the adult brain.

Induction of brain-derived neurotrophic factor in enteric glial cells stimulated by interleukin-1β via a c-Jun N-terminal kinase pathway.

Brain-derived neurotrophic factor exhibits neurotropic and neuroprotective functions and is increased in the colonic mucosa of patients with irritable bowel syndrome in correlation with the severity and frequency of abdominal pain. However, there are no reports of brain-derived neurotrophic factor expression in enteric glial cells. We evaluated the mRNA and protein expressions of brain-derived neurotrophic factor in enteric glial cells and culture medium and levels of mitogen-activated protein kinase after stimulation with interleukin-1β. Brain-derived neurotrophic factor mRNA expression was increased by interleukin-1β (3.125-75ng/ml) and time-dependently increased 3-fold (24h) and 4-fold (48h) by interleukin-1β (50ng/ml). Pro- and mature brain-derived neurotrophic factor proteins were both significantly increased at 48h by interleukin-1β. However, the mature form was predominant in the cultured medium. Interleukin-1β increased phosphorylated-p38 mitogen-activated protein kinase expressions 2-fold higher at 5 and 15min, and also phosphorylated-c-Jun N-terminal kinase expression 5-fold at 5min and 10-fold at 15min. Prior treatment with phosphorylated-c-Jun N-terminal kinase inhibitors decreased interleukin-1β-induced brain-derived neurotrophic factor by 50%. Thus, brain-derived neurotrophic factor expression was induced by interleukin-1β in enteric glial cells via a phosphorylated-c-Jun N-terminal kinase pathway, which might affect the enteric nervous system during stress.

Low Intensity Pulsed Ultrasound Prevents Recurrent Ischemic Stroke in a Cerebral Ischemia/Reperfusion Injury Mouse Model via Brain-derived Neurotrophic Factor Induction

The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke.

Sa1688 – Induction of Brain-Derived Neurotrophic Factor in Enteric Glial Cells Stimulated by Interleukin-1Β

Sa1688 – Induction of Brain-Derived Neurotrophic Factor in Enteric Glial Cells Stimulated by Interleukin-1Β

Citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone induces BDNF via cAMP/ERK/CREB signaling and reduces phosphodiesterase activity in C6 cells.

Brain-derived neurotrophic factor (BDNF) is associated with onset of several central nervous system disorders, e.g., Parkinson's disease, Alzheimer's disease, depression, epilepsy, and chronic pain. In our previous in vivo studies using ischemic and depression mouse models, we revealed that citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) exerts neuroprotective effects by enhancing the expression of BDNF in astrocytes within the hippocampus. Therefore, in the present study, we examined the mechanism of BDNF induction by HMF in vitro using rat C6 glioma cells. C6 glioma cells were treated with HMF (10 μM) or HMF + U0126 (10 μM), HMF + H89 (1 μM), or HMF + K252a (200 nM) for 48 h. The protein level of mature BDNF (m-BDNF), phosphorylated-ERK (p-ERK) and phosphorylated-cAMP-response element binding protein (p-CREB) were measured using western blot analysis. To clarify the mechanism of HMF for increasing m-BDNF, the inhibitory effect of phosphodiesterase 4B (PDE4B) and PDE4D, and intracellular cAMP levels were examined by ELISA. Our findings revealed that the m-BDNF-inducing activity of HMF was abolished by U0126 but not by H89 or K252a. HMF was found to phosphorylate (activate) ERK and cAMP-response element binding protein (CREB), a BDNF transcription factor. HMF inhibited PDE4B and PDE4D activity. Moreover, 10 μM HMF elevated intracellular cAMP levels in C6 cells. These findings suggest that HMF might exert its neuroprotective effects by inducing m-BDNF expression in C6 cells, model cell line of astrocytes, via the activation of cAMP/ERK/CREB signaling and inhibiting PDE4B or PDE4D.

Hippocampal activation of 5-HT1B receptors and BDNF production by vagus nerve stimulation in rats under chronic restraint stress.

A growing body of evidence shows that the electrical stimulation of the vagus nerve can improve mental illness including depression. Here, we investigated whether the vagus nerve stimulation (VNS) is involved in regulating the responsiveness of hippocampal neurons in rats under chronic restraint stress (CRS). c-Fos protein signals were detected 2hr after VNS in 5-HT1A receptor-positive neurons in the dorsal raphe nucleus (DRN) as well as in the nucleus tractus solitarius (NTS). Chronic VNS was performed on a daily basis for 2weeks using an implanted microelectrode in rats that had undergone CRS for 2weeks. We found that the levels of both 5-HT1B receptors and phospho-Erk1/2 were decreased in parallel in the hippocampal neurons of CRS animals and then increased to the baseline levels by chronic VNS. Hippocampal induction of 5-HT1B receptors and phospho-Erk1/2 by VNS was diminished after the injection of 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin of serotonergic neurons, into the DRN. Hippocampal production of brain-derived neurotrophic factor (BDNF) was also upregulated by VNS, but the treatment of 5,7-DHT abrogated the effects of VNS on BDNF induction. VNS in CRS animals improved the behavioral scores in forced swimming test (FST) compared to sham-stimulated control. Our results suggest that VNS-mediated serotonergic input via 5-HT1B receptors into the hippocampal neurons may activate BDNF pathway and improve depressive-like behaviors in CRS animals.

Acute and subsequent continuation electroconvulsive therapy elevates serum BDNF levels in patients with major depression

IntroductionThe induction of brain-derived neurotrophic factor (BDNF) release and subsequent restoration of neuroplastic homeostasis may underlie the effects of electroconvulsive therapy (ECT). ObjectivesWe aimed to assess serum and plasma BDNF levels during the course of acute ECT, as well as before and after subsequent continuation ECT, in patients with depression. MethodsWe included 24 patients with major depressive disorder (mean age ± SD: 54.5 ± 13.7; f/m: 17/7; baseline 17-item Hamilton Depression Rating Scale score of 26.79 ± 4.01). Serum and plasma BDNF (sBDNF, pBDNF) levels were assessed at nine time-points before, during, and after acute ECT series. Data were analysed using linear regression and linear mixed models, which were adjusted for multiple comparisons via Bonferroni correction. Five patients received continuation ECT subsequent to the acute ECT series. In these patients, BDNF levels were assessed before and after each two continuation ECT sessions using Wilcoxon signed-rank tests. ResultsRelative to baseline (mean ng/ml ±SD: 24.68 ± 14.40), sBDNF levels were significantly higher 1 day (33.04 ± 14.11, p = 0.013, corrected), 1 week (37.03 ± 10.29, p < 0.001, corrected), and 1 month (41.05 ± 10.67, p = 0.008, corrected) after the final ECT session, while pBDNF levels did not significantly differ (p > 0.1). Furthermore, our results indicated that sBDNF levels increased after each continuation ECT session. There was no significant association between sBDNF levels and clinical parameters or treatment response. ConclusionThe absence of an association between changes in sBDNF levels and depressive symptoms challenges the proposed concept of sBDNF/pBDNF as key markers of the effects of ECT.

Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF).

Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.SIGNIFICANCE STATEMENT It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."

Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor

BackgroundActivity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) is essential for the rapid and sustained antidepressant actions of ketamine, and a recent study shows a similar requirement for vascular endothelial growth factor (VEGF). Since BDNF is reported to stimulate VEGF expression and/or release in neuroblastoma cells, the present study tested the hypothesis that the actions of BDNF are mediated by VEGF. MethodsThe role of VEGF in the antidepressant behavioral actions of BDNF was tested by intra-mPFC coinfusion of a VEGF neutralizing antibody and by neuron-specific deletion of VEGF. The influence of BDNF on the release of VEGF and the role of VEGF in the neurotrophic actions of BDNF were determined in rat primary cortical neurons. The role of BDNF in the behavioral and neurotrophic actions of VEGF was also determined. ResultsThe results show that the rapid and sustained antidepressant-like actions of intra-mPFC BDNF are blocked by coinfusion of a VEGF neutralizing antibody, and that neuron-specific mPFC deletion of VEGF blocks the antidepressant-like actions of BDNF. Studies in primary cortical neurons demonstrate that BDNF stimulates the release of VEGF and that BDNF induction of dendrite complexity is blocked by a selective VEGF–fetal liver kinase 1 receptor antagonist. Surprisingly, the results also show reciprocal interactions, indicating that the behavioral and neurotrophic actions of VEGF are dependent on BDNF. ConclusionsThese findings indicate that the antidepressant-like and neurotrophic actions of BDNF require VEGF signaling, but they also demonstrate reciprocal interdependence for BDNF in the actions of VEGF.

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR.

Methylene blue protects dopaminergic neurons against MPTP-induced neurotoxicity by upregulating brain-derived neurotrophic factor.

The relatively old, yet clinically used, drug methylene blue (MB) is known to possess neuroprotective properties by reducing aggregated proteins, augmenting the antioxidant response, and enhancing mitochondrial function and survival in various models of neurodegenerative diseases. In this study, we aimed to examine the effects of MB in Parkinson's disease (PD) in vivo and in vitro models by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+ ) with a focus on possible effects on induction of neurotrophic factors. Our results indicate that pretreatment with MB significantly attenuated MPTP-induced loss of dopaminergic neurons, glial cell activation, and depletion of dopamine. We also found that MB upregulated brain-derived neurotrophic factor (BDNF) and activated its downstream signaling pathways, suggesting that BDNF might be a contributor to MB-associated neuroprotection. Specific inhibition of the BDNF receptor or extracellular signal-regulated kinase (Erk) reversed the MB-mediated protection against MPP+ toxicity, thus implying a role for BDNF and the Erk pathway in the neuroprotective effects. Taken together, our data suggest that MB protects neurons from MPTP neurotoxicity via induction of BDNF. Further study to determine whether MB preserves dopaminergic neurons in the brains of PD patients is warranted.

Electroconvulsive seizures influence dendritic spine morphology and BDNF expression in a neuroendocrine model of depression

BackgroundElectroconvulsive therapy (ECT) is a rapid and effective treatment for major depressive disorder. Chronic stress-induced depression causes dendrite atrophy and deficiencies in brain-derived neurotrophic factor (BDNF), which are reversed by anti-depressant drugs. Electroconvulsive seizures (ECS), an animal model of ECT, robustly increase BDNF expression and stimulate dendritic outgrowth. ObjectiveThe present study aims to understand cellular and molecular plasticity mechanisms contributing to the efficacy of ECS following chronic stress-induced depression. MethodsWe quantify Bdnf transcript levels and dendritic spine density and morphology on cortical pyramidal neurons in mice exposed to vehicle or corticosterone and receiving either Sham or ECS treatment. ResultsECS rescues corticosterone-induced defects in spine morphology and elevates Bdnf exon 1 and exon 4-containing transcripts in cortex. ConclusionsDendritic spine remodeling and induction of activity-induced BDNF in the cortex represent important cellular and molecular plasticity mechanisms underlying the efficacy of ECS for treatment of chronic stress-induced depression.