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Hypoxic/ischemic (HI) brain damage (HIBD) is a major cause of acute neonatal brain injury, leading to high mortality and serious neurological deficits. The antisense RNA of brain-derived neurotrophic factor (BDNF-AS) is transcribed from the opposite strand of the BDNF gene. The aim of the present study was to investigate the role of BDNF-AS in HI-induced neuronal cell injury in vivo and in vitro. Reverse transcription-quantitative PCR (RT-qPCR) assays indicated that BDNF-AS expression was significantly upregulated in HI-injured neonatal brains and hippocampal neurons. However, BDNF expression was downregulated in HI-injured neonatal brains and hippocampal neurons. Cell Counting Kit-8 assays, Hoechst staining, calcein-AM/PI staining, immunostaining, water maze tests and rotarod tests demonstrated that BDNF-AS silencing protected against hypoxia-induced primary hippocampal neuron injury in vitro and HI-induced brain injury in vivo. Mechanistically, RT-qPCR assays and western blotting indicated that BDNF-AS silencing led to increased expression of BDNF and activated the BDNF-mediated signaling pathway, as demonstrated by increased expression levels of BDNF, phosphorylated-Akt and phosphorylated-tropomyosin receptor kinase B. Collectively, the present study provides important insights into the pathogenesis of HIBD, and it was indicated that BDNF-AS silencing may be a promising approach for the treatment of neonatal HIBD.

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors that regulate the development of the central nervous system during fetal growth. Apart from its role in neurogenesis, BDNF, along with its high-affinity receptor tropomyosin-related receptor kinase B (TrkB), serves a key role in the pathogenesis of several tumors such as breast, cervical and colorectal cancer, and gliomas. The oncogenic effects of BDNF and TrkB upregulation, including effects on the aggressiveness, metastatic potential and resistance to standard chemotherapeutic agents, are mediated by the downstream activation of the PI3K/Akt pathway, EGFR activation and MAPK pathways. In view of the key role served by BDNF and TrkB in various steps of oncogenesis, there have been attempts to develop inhibitors of the TrkB receptor to block the effects of BDNF upregulation, and these have shown promising results. The role of the BDNF-TrkB pathway in the pathogenesis of gallbladder cancer (GBC), a biliary tract malignancy with high mortality, has still not been fully elucidated. Immunohistochemical expression of TrkB at the invasive front of GBC has been demonstrated along with the growth inhibitory effect of TrkB siRNA on GBC cell lines, suggesting the role of this pathway in the aggressiveness of GBC. The present review explores the mechanisms of action of the BDNF-TrkB axis, focusing on GBC, in an attempt to provide future research directions for delineating the role of this pathway in the pathogenesis of GBC and the potential therapeutic implications.

Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

Key Points Neurotrophins bind to several combinations of cell surface receptors to regulate neuronal survival, function and plasticity. The p75 neurotrophin receptor has numerous functions and is not just a 'death' receptor; under some circumstances it may counteract neurodegenerative signalling. Potential factors that limit the application of neurotrophins as neurological therapeutics include their limited stability, poor central nervous system (CNS) bioavailability, binding to multiple (rather than individual) neurotrophin receptors and mechanism-based side effects. Studies using synthetic oligopeptides have demonstrated the feasibility of creating small molecules that can act as ligands for neurotrophin receptors. Small-molecule ligands can be targeted to specific neurotrophin receptors to modulate signalling. Ligands have been developed that mimic, partially mimic or inhibit the actions of neurotrophins and, importantly, achieve effects that are distinct from those of neurotrophins. Small-molecule modulation of neurotrophin receptor signalling can correct or counteract the deleterious intracellular signalling patterns that exist in various neuropathological states. The administration of small-molecule ligands to several in vivo neurological disease models can correct neuropathological and behavioural abnormalities. Small-molecule ligands are in early stages of clinical development. Although neurotrophins could provide benefit in neurological diseases, their therapeutic application is limited by poor pharmacological properties and undesirable pleiotropic actions. Here, Longo and Massa highlight recent progress in the targeting of individual neurotrophin receptors using small-molecule ligands in an effort to overcome these limitations. Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.

Globally, neurodegenerative diseases cause a significant degree of disability and distress. Brain-derived neurotrophic factor (BDNF), primarily found in the brain, has a substantial role in the development and maintenance of various nerve roles and is associated with the family of neurotrophins, including neuronal growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). BDNF has affinity with tropomyosin receptor kinase B (TrKB), which is found in the brain in large amounts and is expressed in several cells. Several studies have shown that decrease in BDNF causes an imbalance in neuronal functioning and survival. Moreover, BDNF has several important roles, such as improving synaptic plasticity and contributing to long-lasting memory formation. BDNF has been linked to the pathology of the most common neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. This review aims to describe recent efforts to understand the connection between the level of BDNF and neurodegenerative diseases. Several studies have shown that a high level of BDNF is associated with a lower risk for developing a neurodegenerative disease.

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin, acting as a neurotrophic signal and neuromodulator in the central nervous system (CNS). BDNF is synthesized from its precursor proBDNF within the CNS and peripheral tissues. Through activation of NTRK2/TRKB (neurotrophic receptor tyrosine kinase 2), BDNF promotes neuronal survival, synaptic plasticity, and neuronal growth, whereas it inhibits microglial activation and the release of pro‐inflammatory cytokines. BDNF is dysregulated in different neurodegenerative diseases and depressions. However, there is a major controversy concerning BDNF levels in the different stages of multiple sclerosis (MS). Therefore, this review discusses the potential role of BDNF signaling in stages of MS, and how BDNF modulators affect the pathogenesis and outcomes of this disease. Brain‐derived neurotrophic factor (BDNF) is crucial for neuronal survival and plasticity in the CNS, acting through NTRK2/TRKB receptors. It also plays a role in inhibiting microglial activation and pro‐inflammatory cytokine release. This review examines the controversial BDNF levels in multiple sclerosis (MS) stages and explores how BDNF signaling and its modulators influence MS pathogenesis and outcomes.

RationaleThe volatile anesthetic isoflurane is suggested to produce a rapid and robust antidepressive effect in preliminary clinical trials. Recently, isoflurane was found to activate the tropomyosin receptor kinase B (TrkB) signaling which is the underlying mechanism of the rapid antidepressant ketamine.ObjectiveOur study investigated the effect of isoflurane anesthesia on chronic unpredictable mild stressed (CUMS) model in mice and verified the role of brain-derived neurotrophic factor (BDNF)/TrkB/ the mammalian target of rapamycin (mTOR) signaling in the antidepressant effect of isoflurane.MethodsWe employed the CUMS model of depression to assess the rapid antidepressant effect of isoflurane by the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). The protein expression of BDNF and TrkB/protein kinase B (PKB or Akt)/mTOR was determined through Western blot. The dendritic spine density in the hippocampus and medial prefrontal cortex (PFC) was measured by the Golgi staining.ResultsA brief burst-suppressing isoflurane anesthesia rapidly reversed the behavioral deficits caused by CUMS procedure, normalized the expression of BDNF and further activated the TrkB signaling pathway in CUMS-induced stressed mice in both prefrontal cortex (PFC) and hippocampus (HC). All of those behavioral and proteomic effects were blocked by K252a, a selective receptor inhibitor of TrkB. Isoflurane significantly promoted the formation of dendritic spines in both medial prefrontal cortex (mPFC), CA1, CA3, and DG of the hippocampus.ConclusionOur study indicates that isoflurane exerts a rapid antidepressant-like effect in CUMS depression animal model, and the activation of BDNF/TrkB signaling pathway plays an indispensable role in the biological and behavioral antidepressant effects of isoflurane. A single exposure to isoflurane could repair synaptic damage caused by chronic stimulation.

Background Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs). Methods Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells. Results RTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1β, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection. Conclusion These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.

Neurotrophins are a family of growth factors that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4. Among them, BDNF is the most studied due to its high expression in the brain. Over the past two decades, BDNF and its receptor tropomyosin receptor kinase B (TrkB) have been reported to be upregulated in a wide range of tumors. This activated signal stimulates a series of downstream pathways, including phosphoinositide 3-kinase/protein kinase B, Ras-Raf-mitogen activated protein kinase kinase-extracellular signal-regulated kinases, the phospholipase-C-γ pathway and the transactivation of epidermal growth factor receptor. Activation of these signaling pathways induces oncogenic effects by increasing cancer cell growth, proliferation, survival, migration and epithelial to mesenchymal transition, and decreasing anoikis, relapse and chemotherapeutic sensitivity. The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.