Brain-derived Neurotrophic Factor Overexpression Research Articles

MicroRNA-497 inhibits thyroid cancer tumor growth and invasion by suppressing BDNF.

miR-497 reportedly plays critical roles in tumor development and progression in many types of cancers. We therefore investigated the function and underlying mechanism of miR-497 in thyroid cancer. We found that miR-497 is downregulated in thyroid cancer tissues, and that miR-497 levels are negatively correlated with advanced clinical stage and lymph node metastasis. Overexpressed miR-497 suppressed thyroid cancer cell proliferation, colony formation, migration, and invasion in vitro, and inhibited tumorigenesis in vivo. Moreover, brain-derived neurotrophic factor (BDNF), a known oncogene, was confirmed as a direct target of miR-497 in thyroid cancer cells. miR-497 overexpression suppressed BDNF expression and its downstream pathway(PI3K/AKT)in vitro and in vivo. BDNF levels were upregulated and inversely correlated with miR-497 levels in human thyroid cancer specimens. Rescue experiments showed that forced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-497. These results show that miR-497 is a thyroid cancer tumor suppressor that acts by repressing BDNF.

MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer.

Abnormal expression of microRNA-107 (miR-107) was found in non-small cell lung cancer (NSCLC). However, little is known about its role and molecular mechanism in NSCLC progression and metastasis. Therefore, the aims of this study were to clarify the potential role of miR-107 and molecular mechanism in NSCLC progression and metastasis. Quantitative real-time polymerase chain reaction assay showed that miR-107 expression levels were significantly decreased in NSCLC tissue and cell lines. Low miR-107 levels in tumor tissue correlated with advanced TNM stage and lymph node metastasis. Function assays showed that overexpression of miR-107 suppressed cell proliferation, migration and invasion in A549 cells in vitro, and inhibited NSCLC tumor growth in vivo. Further mechanism assays suggested the brain-derived neurotrophic factor (BDNF) was identified as a target gene of miR-107 in NSCLC cells. In addition, BDNF expression was upregulated, and inversely correlated with miR-107 in NSCLC tissues. Enforced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-107 on NSCLC proliferation, migration and invasion. miR-107 overexpression or downregulation of BDNF was able to inhibit activation of PI3K/AKT signaling pathway. Taken together, our findings present the first evidence that miR-107 could suppress NSCLC metastasis by targeting BDNF and indirectly regulating PI3K/AKT signaling pathway, which might lead to a potential therapeutic strategy focusing on miR-107 and BDNF for human NSCLC.

Long-Term Protection of Retinal Ganglion Cells and Visual Function by Brain-Derived Neurotrophic Factor in Mice With Ocular Hypertension.

PurposeGlaucoma, frequently associated with elevated intraocular pressure (IOP), is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Brain-derived neurotrophic factor (BDNF) has been studied as a candidate for neuroprotection in rodent models of experimental glaucoma, yet it remains to be determined whether BDNF exerts long-term protection for subtype RGCs and vision against chronic IOP elevation.MethodsWe induced modest and sustained IOP elevation by laser illumination and microbead injection in mice. Using a tamoxifen-induced Cre recombinase system, BDNF was upregulated in the mouse retina when sustained IOP elevation was induced. We then examined whether overexpression of BDNF protected RGCs and vision during the period of ocular hypertension. Given that BDNF modulates axon growth and dendritic formation in a subtype-dependent manner, we tested whether BDNF protects RGC dendritic structure against the hypertensive insult also in a subtype-dependent manner.ResultsSustained IOP elevation was induced and lasted up to 6 months. Overexpression of BDNF delayed progressive RGC and axon loss in hypertensive eyes. Brain-derived neurotrophic factor overexpression also helped to preserve acuity against the chronic hypertensive insult. We classified RGCs into ON and ON–OFF subtypes based on their dendritic lamination pattern in the inner plexiform layer and found that BDNF prevented ON–RGC dendritic degeneration in mice with sustained ocular hypertension.ConclusionsOur data demonstrated that BDNF can protect the dendritic fields of ON RGCs and reduce RGC and vision loss in mice with sustained ocular hypertension.

Translation of BDNF-gene transcripts with short 3′ UTR in hippocampal CA1 neurons improves memory formation and enhances synaptic plasticity-relevant signaling pathways

While the brain-derived neurotrophic factor (BDNF) gene and its multiple transcripts have been recognized as a key factor for learning, but the specific involvement of BDNF translated from BDNF transcripts with short-3′ untranslated region (short 3′ UTR) in learning and memory requires further analysis. In this paper, we present data to show that the transduction of hippocampal CA1 neurons with AAV9-5′ UTR-BDNF (short 3′ UTR)–IRES-ZsGreen and the subsequent expression of BDNF enhanced the phosphorylation of synaptic plasticity relevant proteins and improved passive avoidance and object location, but not object recognition memory. In addition, BDNF improved the relearning of object location. At higher BDNF overexpression levels, the fear behavior was accompanied with a decline in the passive avoidance memory 24h post training, and with an enhanced fear conditioning performance. In addition, these animals developed spontaneous seizures. Thus, the expression of BDNF in the hippocampal CA1 region has the potential to improve fear and object location memory in wild type mouse strains when the region and expression levels of BDNF are well controlled.

Expression of TRPC6 and BDNF in Cortical Lesions From Patients With Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) likely results from abnormal migration of neural progenitor cells originating from the subventricular zone. To elucidate the roles in molecules that are involved in neural migration pathway abnormalities in FCDs, we investigated the expression patterns of transient receptor potential canonical channel 6 (TRPC6) and brain-derived neurotrophic factor (BDNF) in cortical lesions from FCD patients and in samples of normal control cortex. TRPC6 and BDNF mRNA and protein levels were increased in FCD lesions. By immunohistochemistry, they were strongly expressed in microcolumns, heterotopic neurons, dysmorphic neurons, and balloon cells (BCs). Colocalization assays revealed that most of the misshapen TRPC6-positive or heterotopic cells had a neuronal lineage with the exception of TRPC6-positive FCDiib patient BCs, which had both neuronal and glial features. Most TRPC6-positive cells were glutamatergic neurons. There was also greater expression of calmodulin-dependent kinase IV (CaMKIV), the downstream factor of TRPC6, in FCD lesions, suggesting that TRPC6 expression promoted dendritic growth and the development of dendritic spines and excitatory synapses via the CaMKIV-CREB pathway in FCD. Thus, overexpression of BDNF and TRPC6 and activation of the TRPC6 signal transduction pathway in cortical lesions of FCD patients may contribute to FC pathogenesis and epileptogenesis.

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway.

Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.

Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.

Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.

Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR.

Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access “binge” cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

Brain‐derived neurotrophic factor (BDNF) acting within the paraventricular nucleus induces blood pressure elevations under permissive control of angiotensin II and mediates pressor responses to acute stress

Brain‐derived neurotrophic factor (BDNF) exerts diverse effects on neuronal function throughout the central nervous system by regulating gene expression, synaptic function and ion channels via its high‐affinity tyrosine kinase receptor TrkB. The paraventricular nucleus of the hypothalamus (PVN) plays a key role in mediating stress‐induced neuroendocrine responses, and here we tested the novel hypothesis that within the PVN, BDNF is a regulator of cardiovascular function during stress that elicits sympathoexcitation and blood pressure elevations in an angiotensin II (Ang II)‐dependent manner. This hypothesis is based on findings that BDNF expression increases rapidly in the PVN during stress and our previous studies demonstrating that overexpression of BDNF in the PVN leads to significant blood pressure elevations that are mediated, at least in part, by Ang II signaling in the PVN. First, to test acute actions of BDNF in the PVN, Sprague Dawley (SD) rats were equipped with femoral artery and vein catheters for the measurement of blood pressure and infusion of drugs under isoflurane anesthesia. After surgical procedures, anesthesia was gradually switched to iv. α‐chloralose (12–20 mg/kg/h) and cardiovascular responses to intra‐PVN injections of BDNF (12.5 ng) were analyzed following intra‐PVN pretreatment with the Ang II‐type 1 receptor (AT1R) inhibitor losartan (10 ng) or vehicle via a double barrel glass micropipette or after ganglionic blockade with hexamethonium (30 mg/kg, iv). BDNF induced marked increases in mean arterial pressure (MAP; peak increase: 31±4 mmHg; n=5) that were significantly attenuated by losartan (peak increase: 7±1 mmHg; n=5, p<0.01) and hexamethonium (peak increase: 10±1 mmHg; n=5, p<0.01) pretreatments. Additional in vitro experiments conducted on freshly isolated PVN brain punches indicated that BDNF (25 μg/mL, 37°C, 30 min incubation) significantly increased phosphorylation of TrkB receptors and that this effect was inhibited by losartan (10 μM) co‐treatment. To test if BDNF‐TrkB signaling in the PVN mediates cardiovascular responses to acute stress, SD rats were equipped with telemetry transmitters to measure blood pressure and received bilateral PVN injections of lentivirus vectors expressing either green fluorescent protein (GFP, for control; n=6) or TrkB.T1, a dominant negative truncated TrkB receptor variant lacking the intracellular tyrosine kinase module, that inhibits TrkB signaling (n=7). Rats were then subjected to acute water stress (15 min in 1‐cm deep, 25°C water) and acute restraint stress (60 min) 3 and 4 wks after vector injections. TrkB.T1 overexpression had no effect on baseline mean arterial pressure (MAP), but significantly reduced peak MAP elevations during water stress (GFP: 36±3 mmHg; TrkB.T1: 18±8 mmHg, p<0.01) and restraint stress (GFP: 42±4 mmHg; TrkB.T1: 30±2 mmHg, p<0.05). In conclusion, these findings indicate that BDNF acting within the PVN acutely increases blood pressure under permissive control of Ang II and AT1R and that this mechanism plays an important role in mediating pressor responses to acute stress.Support or Funding InformationSupported by AHA 11SDG7560022 and UVM start‐up funds.

MP60-06 PATHOGENIC ROLE OF TRUNCATED TRKB RECEPTOR ISOFORM (TRKB.T1) IN BDNF INDUCED DETRUSOR OVERACTIVITY (DO)

INTRODUCTION AND OBJECTIVES: Overexpression of brain derived neurotrophic factor (BDNF) is well known in overactive bladder (OAB). Amelioration of cyclophosphamide induced DO by antibody mediated sequestration of BDNF highlighted the pathogenic role of BDNF receptors and their downstream signaling. Tropomyosin receptor kinase B (TrkB) is the high affinity receptor for BDNF, which is either expressed as a full length receptor (TrkB FL) or as a splice variant called truncated, TrkB (TrkB.T1). Here, we tested whether gene silencing targeted for TrkB.T1 can overcome the BDNF induced DO. METHODS: Under isoflurane anesthesia, the bladder wall of female Sprague-dawley rats was injected with BDNF plasmid complexed with liposomes (n1⁄45) alone (10mg) or together with either antisense (n1⁄45) or scrambled oligonucleotide against TrkB.T1 (n1⁄45). 7 days later, cystometry was performed followed by bladder harvest to analyze the expression of small Rho GTPase and phosphorylation of Myosin light chain (MLC). RESULTS: As reported earlier, bladder wall injection of BDNF plasmid complexed with liposomes causes BDNF overexpression and DO is observed 7 days later. BDNF induced DO is evident from reduced intercontractile intervals (ICI) and voided volume in rat group injected with BDNF plasmid + scrambled oligonucleotide. In contrast, gene silencing of TrkB.T1 by antisense significantly reversed the DO and increased the ICI and voided urine volume. DO in the scrambled group was associated with the higher expression of Rho kinases viz., RhoA, Cdc42, Rac1 along with the increase phosphorylation of pMLC at Th18 and Ser 19 position. Gene silencing of TrkB.T1 reduced the expression of Rho kinases and completely blocked the phosphorylation of MLC at both positions. CONCLUSIONS: Here, we report that BDNF induced DO is primarily driven by the dominant negative characteristic of TrkB.T1. The tyrosine kinase domain of full length TrkB FL is missing in TrkB.T1, but there exists a domain which interacts with RhoGDi proteins and regulates cell contractility via Rho kinase-mediated increase in phosphorylation of MLC. The C-terminal sequence of TrkB is completely conserved in mammals and therefore verification of TrkB.T1 expression in bladder biopsy of OAB patients is the appropriate next step to establish it as a drug target for treating voiding dysfunctions.

MP68-05 COMPARISON OF THE EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND NERVE GROWTH FACTOR (NGF) INHIBITION ON BLADDER FUNCTION OF MICE WITH SPINAL CORD INJURY (SCI)

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology II1 Apr 2016MP68-05 COMPARISON OF THE EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND NERVE GROWTH FACTOR (NGF) INHIBITION ON BLADDER FUNCTION OF MICE WITH SPINAL CORD INJURY (SCI) Naoki Wada, Takahiro Shimizu, Shun Takai, Nobutaka Shimizu, Pradeep Tyagi, William de Groat, Anthony Kanai, Hidehiro Kakizaki, and Naoki Yoshimura Naoki WadaNaoki Wada More articles by this author , Takahiro ShimizuTakahiro Shimizu More articles by this author , Shun TakaiShun Takai More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Pradeep TyagiPradeep Tyagi More articles by this author , William de GroatWilliam de Groat More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Hidehiro KakizakiHidehiro Kakizaki More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1342AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES BDNF and NGF are reportedly involved in changes in neural pathways to induce lower urinary tract (LUT) dysfunction such as detrusor overactivity (DO) and inefficient voiding following SCI. However, it has not been well clarified how these two growth factors differentially affect storage and voiding functions after SCI. Therefore, we investigated the effects of anti-NGF or anti-BDNF antibody treatment on cystometric parameters in SCI mice. METHODS SCI was produced by complete transection of the Th8/9 spinal cord in female C57BL/6N mice. Three weeks later, an osmotic pump was placed subcutaneously to administer vehicle (group A), 10µg/kg/hr of anti-BDNF antibody (group B) or 10µg/kg/hr of anti-NGF antibody (group C) for 1 week. Four weeks after transection, SCI mice were evaluated using continuous or single-filling cystometry under an awake condition. RESULTS In continuous cystometry, voiding efficiency was significantly increased in the groups B (21%) and C (26%) compared to the group A (14%), and postvoid residual volume (PVR) was lower in the group C (0.14ml) vs. the group A (0.25ml). There was also a tendency of the reduction in non-voiding contractions (NVC) in the group C without statistical significance. Micturition pressure (MP) or intercontraction intervals were not different among the groups. In single cystometry, voided volume (0.085 vs. 0.038 ml) and voiding efficiency (42% vs. 18%) in the group B were significantly increased compared to the group A, and PVR of the group C was lower than that of the group A (0.11 vs. 0.15 ml). MP, maximum cystometric capacity or NVC was not different among groups. CONCLUSIONS Both anti-BDNF and anti-NGF antibody treatments improved voiding dysfunction as shown by increased voiding efficiency due to increased voided volume or decreased PVR in SCI mice. In addition, the anti-NGF, but not anti-BDNF, treatment marginally improved NVCs. These results suggest that BDNF and NGF are involved in SCI-induced voiding dysfunction resulting in inefficient voiding, but have minor roles in storage dysfunction to induce DO in mice, in contrast to the previous findings in SCI rats showing the greater contribution of bladder NGF or BDNF overexpression to DO. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e890-e891 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Naoki Wada More articles by this author Takahiro Shimizu More articles by this author Shun Takai More articles by this author Nobutaka Shimizu More articles by this author Pradeep Tyagi More articles by this author William de Groat More articles by this author Anthony Kanai More articles by this author Hidehiro Kakizaki More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

BDNF acting in the hypothalamus induces acute pressor responses under permissive control of angiotensin II

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during hypertensive stimuli including stress and hyperosmolarity, but its role in PVN cardiovascular regulatory mechanisms is unclear. Chronic BDNF overexpression in the PVN has been shown to elevate sympathetic tone and blood pressure in part by modulating central angiotensin (Ang) II mechanisms. However, the cardiovascular effects of short-term increases in PVN levels of BDNF and the mechanisms governing them are unknown. Therefore, we investigated whether acute BDNF microinjections into the PVN of conscious and anesthetized Sprague-Dawley rats induce blood pressure elevations and whether Ang II signaling is involved in these hypertensive responses. In conscious rats, unilateral BDNF (12.5ng) microinjections into the PVN increased mean arterial pressure (MAP) by 27±1mmHg (P<0.001 vs vehicle), which was significantly attenuated by intracerebroventricular infusion of the Ang II-type-1 receptor (AT1R) antagonist losartan and by ganglionic blockade with intravenous hexamethonium infusion. In anesthetized rats, unilateral PVN microinjection of BDNF increased MAP by 31±4mmHg (P<0.001 vs vehicle), which was prevented by PVN microinjection pretreatments with the high-affinity BDNF receptor TrkB antagonist ANA-12, losartan, the angiotensin converting enzyme inhibitor lisinopril, or by intravenous hexamethonium. Additional experiments in hypothalamic samples including the PVN revealed that BDNF-induced TrkB receptor phosphorylation was prevented by ANA-12 and losartan pretreatments. Collectively, these data indicate that BDNF acting within the PVN acutely raises blood pressure under permissive control of Ang II-AT1R mechanisms and therefore may play an important role in mediating acute pressor responses to hypertensive stimuli.

Regulation of Memory Formation by the Transcription Factor XBP1.

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.

BDNF promotes human neural stem cell growth via GSK-3β-mediated crosstalk with the wnt/β-catenin signaling pathway

Brain-derived neurotrophic factor (BDNF) plays important roles in neural stem cell (NSC) growth. In this study, we investigated whether BDNF exerts its neurotrophic effects through the Wnt/β-catenin signaling pathway in human embryonic spinal cord NSCs (hESC-NSCs) in vitro. We found an increase in hESC-NSC growth by BDNF overexpression. Furthermore, expression of Wnt1, Frizzled1 and Dsh was upregulated, whereas GSK-3β expression was downregulated. In contrast, hESC-NSC growth was decreased by BDNF RNA interference. BDNF, Wnt1 and β-catenin components were all downregulated, whereas GSK-3β was upregulated. Next, we treated hESC-NSCs with 6-bromoindirubin-3′-oxime (BIO), a small molecule inhibitor of GSK-3β. BIO reduced the effects of BDNF upregulation/downregulation on the cell number, soma size and differentiation, and suppressed the effect of BDNF modulation on the Wnt signaling pathway. Our findings suggest that BDNF promotes hESC-NSC growth in vitro through crosstalk with the Wnt/β-catenin signaling pathway, and that this interaction may be mediated by GSK-3β.

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

Background: Brain-derived neurotrophic factor (BDNF) from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. Results: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. Conclusion: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington's disease.

Reduced expression and disrupted corticostriatal transportation of brain-derived neurotrophic factor (BDNF) is proposed to contribute to the selective vulnerability of medium spiny striatal projection neurons (MSNs) in Huntington's disease (HD). We have previously demonstrated that BDNF overexpression in the quinolinic acid lesioned rat striatum attenuates motor impairment and reduces the extent of MSN cell loss. To further investigate the potential therapeutic properties of BDNF for HD, the current study examines the effect of bilateral AAV1/2-mediated BDNF expression in the striatum of a transgenic rat model of HD. Transfer of the BDNF gene to striatal neurons using an AAV1/2 serotype vector enhanced BDNF protein levels in the striatum. Bilateral BDNF expression attenuated the impairment of both motor and cognitive function when compared with AAV1/2-vehicle- or YFP-treated transgenic HD rats. Interestingly, a gender effect was apparent with female transgenic HD rats exhibiting less functional impairment than males. Quantification of NeuN and DARRP32 immunoreactivity and striatal volume revealed limited disease phenotype between wild type and transgenic HD animals. However, AAV1/2-BDNF-treated transgenic HD rats showed evidence of greater striatal volume and increased NeuN+ cell numbers compared with wild-type vehicle- and AAV1/2-vehicle- or YFP-treated transgenic HD rats. We propose BDNF holds considerable therapeutic potential for alleviating behavioral dysfunction and neuronal degeneration in HD, with further work required to examine the role of BDNF-TrkB signaling and the preservation of axonal and synaptic function.

MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF.

We examined the expression pattern and functional roles of microRNA 15a-5p (miR-15a-5p) in human hepatocellular carcinoma (HCC). Possible miR-15a-5p aberrant expression in HCC cell lines or clinical HCC specimens was examined by quantitative real-time PCR (qRT-PCR). In HCC HepG2 and SNU-182 cells, miR-15a-5p was ectopically overexpressed by lentiviral transduction. Its effect on HCC proliferation, cancer division, and in vivo tumor growth were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle assay, and tumorigenicity assay, respectively. The targeting of miR-15a-5p on its downstream gene, brain-derived neurotrophic factor (BDNF), was examined by dual-luciferase assay, qRT-PCR, and Western blot, respectively. BDNF was then overexpressed in HepG2 and SNU-182 cells to evaluate its selective effect on miR-15a-5p in HCC modulation. MiR-15a-5p is aberrantly downregulated in in vitro HCC cell lines and in vivo HCC clinical specimens. Ectopic overexpression of miR-15a-5p suppressed cancer proliferation, induced cell cycle arrest in HepG2 or SNU-182 cells in vitro, and inhibited HCC tumor growth in vivo. MiR-15a-5p selectively and negatively regulated BDNF at both gene and protein levels in HCC cells. Forced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-15a-5p on HCC proliferation and cell division in vitro. Our study demonstrated that miR-15a-5p is a tumor suppressor in HCC and its regulation is through BDNF in HCC.

Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB.

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies.

MicroRNA‑10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain‑derived neurotrophic factor.

MicroRNAs (miRs) can lead to mRNA degradation or inhibit protein translation through directly binding to the 3'‑untranslational region (UTR) of their target mRNAs. Deregulation of miR‑10b has been reported to be associated with chondrosarcoma. However, the role of miR‑10b in chondrosarcoma cell migration and invasion, as well as the underlying mechanisms, has not been investigated. In the present study, it was demonstrated that miR‑10b was notably downregulated in the JJ012 and SW1353 chondrosarcoma cell lines compared with the TC28a2 normal chondrocyte line. Treatment with DNA demethylating agent 5‑aza‑2'‑deoxycytidine and histone deacetylase inhibitor 4‑phenylbutyric acid, or transfection with miR‑10b mimics promoted the expression of miR‑10b, which further suppressed the migratory and invasive capacities of JJ012 chondrosarcoma cells. Moreover, brain‑derived neurotrophic factor (BDNF) was identified as a novel target of miR‑10b, and its protein expression level was negatively regulated by miR‑10b in JJ012 cells. Furthermore, overexpression of BDNF reversed the inhibitory effect of miR‑10b upregulation on the migration and invasion of JJ012 cells. In addition, the data suggest that matrix metalloproteinase 1 (MMP1) may be involved in the miR‑10b/BDNF‑mediated chondrosarcoma cell migration and invasion in JJ012 cells. In conclusion, these findings suggest that miR‑10b/BDNF may serve as a potential therapeutic target for chondrosarcoma.