TrkB Research Articles

Abdominal LIPUS Stimulation Prevents Cognitive Decline in Hind Limb Unloaded Mice by Regulating Gut Microbiota.

Weightlessness usually causes disruption of the gut microbiota and impairs cognitive function. There is a close connection between gut microbiota and neurological diseases. Low-intensity pulsed ultrasound (LIPUS) has a beneficial effect on reducing intestinal inflammation. So we wondered if abdominal LIPUS stimulation can have a positive impact on weightlessness induced cognitive decline by reducing intestinal dysfunction. The findings revealed that the hind limb unloaded mice exhibited evident disruption in intestinal structure and gut microbial homeostasis, along with impairment in their learning and memory capabilities. However, 4-week abdominal LIPUS treatment improved intestinal function in hind limb unloaded mice, characterized by upregulation of tight junction proteins ZO-1 and Occludin expression in the colon, increased diversity and abundance of intestinal microbiota, decreased serum lipopolysaccharide (LPS), and increased short chain fatty acids in colon contents. The hind limb unloaded mice treated with LIPUS exhibited heightened activity levels, improved exploratory tendencies, and significantly enhanced learning and memory faculties, and elevated expression of neuroadaptation-related proteins such as PSD95, GAP43, P-CREB, BDNF, and its receptor TRKB in the hippocampus. Furthermore, the hind limb unloaded mice receiving fecal transplants from the mice whose abdomens were irradiated with LIPUS displayed enhanced cognitive abilities and improved intestinal structure, akin to the outcomes observed in hind limb unloaded mice who received LIPUS abdominal treatment directly. The above results indicate that LIPUS enhances intestinal structure and microbiota, which helps alleviate cognitive impairment caused by weightlessness. LIPUS could be a potential strategy to simultaneously improve gut dysfunction and cognitive decline in astronauts or bedridden patients.

TrkB Receptor Antagonism Enhances Insulin Secretion and Increases Pancreatic Islet Size in Rats Fed a Cafeteria-Style Diet.

Background: In recent years, the role of neurotrophins and their receptors in peripheral tissues has been of great interest. At a metabolic level, the brain-derived neurotrophic factor (BDNF) and its receptor trkB have been reported to participate in insulin secretion from the pancreas in response to increases in circulating blood glucose. Objetive: To determines the role of the BDNF-trkB pathway in insulin secretion and pancreatic morphology in rats fed a cafeteria-style diet for 16 weeks. Methods: For the study, male rats of the Wistar strain were divided into three groups as follows: (1) control group (standard diet), (2) CAF group (cafeteria-style diet) and (3) CAF group treated with ANA-12 (TrkB receptor antagonist). After 4 months of intervention, the glucose and insulin tolerance curves, serum insulin levels, body fat and hematoxylin-eosin staining pancreas were evaluated. Results: The results showed that the cafeteria-style diet induced an increase in the amount of body fat, alterations in the glucose tolerance curve, increased insulin circulation levels, increased HOMA indices and increased pancreatic islet size. The antagonism of the trkB receptor in the rats fed a cafeteria-style diet enhanced some effects such as the accumulation of body fat and insulin secretion and induced a greater increase in the pancreas islet size. Conclusions: Under conditions of cafeteria-style diet-induced obesity, the antagonism of the BDNF-trkB pathway had no enhanced effect on the increase in insulin secretion or pancreatic islet size.

Neurotrophomodulatory effect of TNF-α through NF-κB in rat cortical astrocytes.

Tumor necrosis factor alpha (TNF-α) is a well-known pro-inflammatory cytokine originally recognized for its ability to induce apoptosis and cell death. However, recent research has revealed that TNF-α also plays a crucial role as a mediator of cell survival, influencing a wide range of cellular functions. The signaling of TNF-α is mediated through two distinct receptors, TNFR1 and TNFR2, which trigger various intracellular pathways, including NF-κB, JNK, and caspase signaling cascades. Both TNFR1 and TNFR2 are expressed in astrocytes, which are specialized glial cells essential for maintaining the structural and functional integrity of the central nervous system (CNS). Astrocytes support neuronal function by regulating brain homeostasis, maintaining synaptic function, and supplying metabolic substrates. In addition, astrocytes are known to secrete a variety of growth factors and neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. These neurotrophins play a critical role in supporting neuronal survival, synaptic plasticity, and myelination within the brain. The present study focuses on the role of TNF-α in modulating neurotrophin expression and secretion in rat cortical astrocytes. We demonstrate that TNF-α induces the upregulation of neurotrophins, particularly NGF and BDNF, in cultured astrocytes. This effect is accompanied by an increase in the expression of their respective receptors (TrkA & TrkB), further suggesting a functional modulation of neurotrophic signaling pathways. Notably, we show that the modulation of neurotrophin expression by TNF-α is mediated via the NF-κB signaling pathway. Additionally, we observed that TNF-α also regulates the secretion levels of NGF and BDNF into the culture media of astrocytes in a dose-dependent manner, indicating that TNF-α can modulate both the production and release of these growth factors. Taken together, our findings highlight a previously underexplored neuroprotective role of TNF-α in astrocytes. Specifically, we propose that TNF-α, through the upregulation of neurotrophins, may contribute to maintaining neuronal health and supporting neuroprotection under disease conditions.

Effects of Edgeworthia chrysantha Lindl. Extract on BDNF and its Receptor TrkB in the Hippocampus of Depression Model Rats

Effects of <i>Edgeworthia chrysantha Lindl.</i> Extract on BDNF and its Receptor TrkB in the Hippocampus of Depression Model Rats

Bifidobacterium bifidum CCFM1359 alleviates intestinal motility disorders through the BDNF-TrkB pathway.

Intestinal motility disorder is characterised by abnormal intestinal motility function, often resulting in symptoms such as diarrhoea and constipation. Probiotics are increasingly recognised as an effective treatment for gastrointestinal disorders, including intestinal motility disorders. In this study, we used senna extract to induce an animal model of intestinal dysfunction characterised by BDNF downregulation. By assessing relevant indicators of intestinal dyskinesia, we found that Bifidobacterium bifidum CCFM1359 effectively alleviated the dyskinesia. However, this alleviating effect was nullified when a TrkB receptor inhibitor was introduced, suggesting that Bifidobacterium bifidum CCFM1359 operates through the BDNF-TrkB pathway. Further analysis revealed that Bifidobacterium bifidum CCFM1359 likely exerts its beneficial effects by regulating intestinal microecology (increasing the relative abundance of Bifidobacterium bifidum and valeric acid content while decreasing Faecalibacterium and butyric acid content), reducing intestinal inflammation (upregulating the anti-inflammatory factor IL-10 and downregulating pro-inflammatory factors TNF-α and IL-1β), and remodelling intestinal nerves (upregulating S100β and the excitatory neurotransmitter ACh, while downregulating the inhibitory neurotransmitter nNOS). This study provides a theoretical basis for using probiotics to alleviate intestinal motility disorders.

Dexmedetomidine Improves Learning Functions in Male Rats Modeling Cognitive Impairment by Modulating the BDNF/TrkB/CREB Signaling Pathway.

Dexmedetomidine (DEX) is a selective alpha-2 adrenergic receptor agonist with sedative and anxiolytic properties. Increasing evidence reports that DEX has a neuroprotective effect. In this study, we investigated the potential effects of DEX on learning and memory functions in rats with experimental cognitive impairment. In the study, 21 adult male rats were used. The rats were divided into three groups, namely control, Scopolamine (SCOP) and SCOP + DEX. Cognitive impairment was induced with 1 mg/kg SCOP daily for 21 days. DEX was administered at a dose of 10 µg/kg between days 14 and 21 of the experiment. Following the injections, a spatial memory test was performed with a Morris Water Maze (MWM). At the end of the experiment, the hippocampus was dissected. The brain-derived neurotrophic factor (BDNF), acetylcholine (ACh) and acetylcholinesterase (AChE) levels were determined by ELISA. The tropomyosin receptor kinase B (TrkB) and Cyclic AMP-Response Element-Binding Protein (CREB) levels were measured by immunohistochemistry. DEX treatment improved the learning performance of rats compared to SCOP for 5 days. However, it did not significantly change memory performance. DEX increased the BDNF and ACh levels in the hippocampus while decreasing the AChE levels. Similarly, DEX treatment significantly increased CREB phosphorylation. No significant difference was observed between the TrkB receptor levels of the groups. This study demonstrated that the role of DEX in reducing SCOP-induced cognitive impairment is partially mediated by the increase in BDNF/TrkB/CREB signaling pathway activity.

CRISPR-Edited DPSCs, Constitutively Expressing BDNF Enhance Dentin Regeneration in Injured Teeth.

Dental caries is one of the most common health issues worldwide arising from the complex interactions of bacteria. In response to harmful stimuli, desirable outcome for the tooth is the formation of tertiary dentin, a protective reparative process that generates new hard tissue. This reparative dentinogenesis is associated with significant inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs). Previously, we have shown that brain-derived neurotrophic factor (BDNF) and its receptor TrkB, key mediators of neural functions, are activated during the DPSC-mediated dentin regeneration process. In this study, we further define the role of inflammation in this process and apply stem cell engineering to enhance dentin regeneration in injured teeth. Our data show that TrkB expression and activation in DPSCs rapidly increase during odontogenic differentiation, further amplified by inflammatory inducers and mediators such as TNFα, LTA, and LPS. An in vivo dentin formation assessment was conducted using a mouse pulp-capping/caries model, where CRISPR-engineered DPSCs overexpressing BDNF were transplanted into inflamed pulp tissue. This transplantation significantly enhanced dentin regeneration in injured teeth. To further explore potential downstream pathways, we conducted transcriptomic profiling of TNFα-treated DPSCs, both with and without TrkB antagonist CTX-B. The results revealed significant changes in gene expression related to immune response, cytokine signaling, and extracellular matrix interactions. Taken together, our study advances our understanding of the role of BDNF in dental tissue engineering using DPSCs and identifies potential therapeutic avenues for improving dental tissue repair and regeneration strategies.

Anxio-depressive phenotype and impaired memory in mice with a conditional knockout of brain-derived neurotrophic factor in endothelial cells.

The present study investigated the role of endothelial brain-derived neurotrophic factor (BDNF) in cognition. Male adult mice with a selective knockout of BDNF in endothelial cells (BDNFECKO) and their wild-type (WT) littermates were subjected to tests for detection of anxiety- and depression-like behaviors and impaired recognition memory. Neuronal activity and synaptogenesis were assessed from hippocampal levels of c-fos and synaptophysin, respectively, and cerebral capillary density from forebrain levels of CD31. BDNF/TrkB (tropomyosin-related kinase type B) receptor signaling was investigated through hippocampal levels of BDNF and activated TrkB receptors coupled with their immunolabeling by neurons and endothelial cells from both cerebrovascular fractions enriched in capillaries and hippocampal arterioles. Endothelial nitric oxide (NO) production was assessed from the expression of endothelial NO synthase phosphorylated at serine 1177. BDNFECKO mice exhibited anxio-depressive phenotype, impaired memory, and reduced synaptogenesis. Neither neuronal activity, neuronal BDNF/TrkB signaling, nor capillary density differed between BDNFECKO and WT mice. However, endothelial-activated TrkB receptors as well as endothelial NO production and hippocampal BDNF levels were lower in BDNFECKO than those in WT mice. We conclude that endothelial BDNF is involved in cognition through mechanisms independent of neuronal BDNF/TrkB signaling and that endothelial NO might be a driver of the procognitive effect of endothelial BDNF.NEW & NOTEWORTHY The study provides the proof of concept that endothelial brain-derived neurotrophic factor (BDNF) plays a crucial role in postnatal synaptogenesis and development of behavior/memory. It also shows that neuronal tropomyosin-related kinase type B (TrkB) receptors are not a target of endothelium-derived BDNF.

Expression of Neurotrophins and Its Receptors During Fetal Development in the Human Cochlea.

We determined the relative expression levels of the receptors TrkA, TrkB, TrkC, and p75NTR and ligands BDNF, NT-3, NGF, and NT-4 with RNAseq analysis on fetal human inner ear samples, located TrkB and TrkC proteins, and quantified BDNF with in situ hybridization on histological sections between gestational weeks (GW) 9 to 19. Spiral ganglion neurons (SGNs) and satellite glia appear to be the main source of BDNF and synthesis peaks twice at GW10 and GW15-GW17. Tonotopical gradients of BDNF revert between GW8 and GW15 and follow a maturation and innervation density gradient in SGNs. NT-3/TrkC follows the same time course of expression as BDNF/TrkB. Immunostaining reveals that TrkB signaling may act mainly through satellite glia, Schwann cells, and supporting cells of Kölliker's organ, while TrkC signaling targets SGNs and pillar cells in humans. The NT-4 expression is upregulated when BDNF/NT-3 is downregulated, suggesting a balancing effect for sustained TrkB activation during fetal development. The mission of neurotrophins expects nerve fiber guidance, innervation, maturation, and trophic effects. The data shall serve to provide a better understanding of neurotrophic regulation and action in human development and to assess the transferability of neurotrophic regenerative therapy from animal models.

Effects of Ficus exasperata on neurotransmission and expression of BDNF, tau, ACHE and BACE in diabetic rats

Diabetes mellitus, a chronic metabolic disorder, has significant global health implications, particularly due to its neurological complications, such as diabetic neuropathy. This condition increases the risk of neurodegenerative diseases by affecting peripheral nerves and cognition. Ficus exasperata, known for its neuroprotective properties, shows promise as a therapeutic option for addressing these complications. This study evaluates the effects of methanol extract of Ficus exasperata (MEFE) on neurotransmission and the expression of Tau, brain-derived neurotrophic factor (BDNF), acetylcholinesterase (ACHE), and Beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) in alloxan-induced diabetic Wistar rats. The controlled experimental design involved 20 Wistar rats divided into four groups (n = 5): control, diabetic untreated, diabetes + MEFE (200 mg/kg), and diabetes + insulin (0.3 IU). The methanol extract was prepared using cold maceration, and an aliquot was subjected to gas chromatography-mass spectrometry. Constituents of MEFE were docked with neurologic receptors. Blood glucose levels were measured using the glucose oxidase method, and neurotransmitter levels, antioxidants, oxidative stress markers, and the expression of Tau, BDNF, ACHE, and BACE were assessed using standard procedures and qRT-PCR. Data were analyzed using one-way ANOVA at P < 0.05. Results indicated that MEFE significantly reduced fasting blood glucose levels compared to untreated diabetic rats. In silico docking identified kaur-16-ene, a constituent of MEFE, as having the highest binding affinity for NMDA, TrkB, mAchR and nAchR receptors, indicating its neuroprotective potential. MEFE also enhanced antioxidant enzyme levels (SOD, GPx, catalase) while reducing oxidative stress markers (MDA, 8-OHdG). Gene expression analysis revealed that MEFE modulates the expression of Tau, BDNF, ACHE, and BACE, suggesting its potential to influence neurodegenerative pathways associated with diabetic neuropathy. Ficus exasperata demonstrates significant therapeutic potential in managing diabetic neuropathy and related cognitive impairments by modulating neurotransmission, protein expression, and antioxidant defenses.

RTMS Modulation of Behavioral and Biological Measures in 3xTg-AD Mice.

The biological basis for behavioral manifestations of Alzheimer's disease remains unclear. Emotional and behavioral alterations of Alzheimer's disease can result in substantial caregiver burden and lack effective management. This study expands upon previous work investigating behavioral alterations in mice with Alzheimer's disease and a potential treatment of increasing brain-derived neurotrophic factor (BDNF) using repetitive transcranial magnetic stimulation (rTMS). A total of 47 3xTg-AD (Alzheimer's) and 53 B6 (wildtype) mice were administered ANA12 (an antagonist of TrkB receptor) or Vehicle (saline) and then rTMS or Sham treatment daily. After 14 days of treatments and injections, mouse behavior was assessed under various behavioral cognitive tests. Mice were then perfused, and brain samples were processed for histology and protein assays. Brain homogenates were analyzed for BDNF and its downstream signaling molecules. Open field testing demonstrated that 3xTg-AD mice spent more time in the center than B6 mice. 3xTg-AD-Sham mice injected with ANA12 were the only group to travel significantly less distance than B6-ANA12-Sham or B6-Vehicle-Sham mice (p < 0.05), while 3xTg-AD-rTMS mice (irrespective of injection) were not significantly different from B6 mice. 3xTg-AD mice had significantly greater measured levels of BDNF and TrkB than the wild-type mice. Treatment of Alzheimer's disease using rTMS positively affects elements of hypoactivity, but not all behavioral abnormalities. rTMS shifted 3xTg-AD open field behavioral test measures, generating significant differences between untreated 3xTg-AD and B6 genotypes. Despite its benefit, further investigation of rTMS as a treatment for Alzheimer's disease as well as its biological underpinnings are needed.

The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction

The most aggressive tumors of human central nervous system are anaplastic astrocytoma (AA, III grade) and glioblastoma multiforme (GBM, IV grade) with an extremely bad prognosis. Their malignant character and resistance to standard therapy are correlated to the over-expression of survival pathways such as Ras/Raf/MEK/ERK and PLCγ1/PKC regulated by TrkB receptor. Therefore, the aim of this study was to investigate the engagement of those pathways in human glioma cells resistance for apoptosis induction by Temozolomide treatment. Two cancer MOGGCCM (AA) and T98G (GBM) and normal human astrocytes (NHA) cell lines were utilized. The tested inhibitors single and simultaneous action with Temozolomide affection on apoptosis induction was analyzed by MTT, microscopic observations and flow cytometry. Bcl-2:beclin-1 complexes occurrence was also assessed. siRNAs were used for direct proof of tested pathways engagement in gliomas resistance to apoptosis elimination. The most effective in eliminating gliomas with minimal astrocyte damage was 5 μM PLCγ1 inhibitor (U-73122) for MOGGCCM and 15 μM for T98G cells, and 1 μM LOXO-101 for all cancer cells. Sorafenib, Temozolomide, U-73122, and LOXO-101 effectively eliminate cancer cells. Single applications of sorafenib and Temozolomide were effective, but had lower efficiency than U-73122 and LOXO-101. These drugs induced apoptosis, affecting mitochondrial membrane potential and caspases 3, 8, and 9 activity. The study found that a Bcl-2:beclin-1 complex formation was observed when apoptosis was dominant. Inhibiting the pathways regulated by TrkB receptor combined with Temozolomide action, led to successful gliomas elimination. Those results might serve as basis for modern targeted treatment development.

Low-Molecular Neurotrophin-3 Mimetics with Different Patterns of Postreceptor Signaling Activation Attenuate Differentially Morphine Withdrawal in Rats

The accumulated evidence suggests that varying levels of tyrosine kinase receptor signaling pathway activity may regulate opiate-associated neuroadaptation of noradrenergic system. Neurotrophin-3 (NT-3) interacts with tropomyosin receptor kinases (TRKs), binding mainly to TRKC receptors, which are expressed within noradrenergic neurons in the blue spot (locus coeruleus, LC). Considering the difficulties in delivering full-length neurotrophins to the CNS after systemic administration, low-molecular mimetics of loop 4 in NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), and hexamethylenediamide bis-(N-γ-oxybutyryl-L-glutamyl-L-asparagine) (GTS-302), activating TRKC and TRKB receptors, were synthesized. The aim of the study is comparative examination of the effects of NT-3 dipeptide mimetics on the signs of morphine withdrawal in outbred white rats with opiate dependence, as well as investigation of activation of postreceptor signaling pathways by the mimetics. Dipeptides GTS-301 and GTS-302 after acute administration at doses of 0.1, 1.0, and 10.0 mg/kg (i.p., intraperitoneal) had a dose-dependent effect on the specific morphine withdrawal symptoms with the most effective dose being 1.0 mg/kg. Maximum decrease in the total index of morphine withdrawal syndrome for GTS-301 was 31.3% and for GTS-302 – 41.4%. Unlike GTS-301, GTS-302 weakened mechanical allodynia induced by morphine withdrawal, reducing tactile sensitivity. When studying activation of the postreceptor signaling pathways by the NT-3 mimetics in the HT-22 hippocampal cell culture, a different pattern of postreceptor signaling was shown: GTS-302 (10−6 M), similar to NT-3, activates all three MAPK/ERK, PI3K/AKT/mTOR, and PLCγ1 pathways, while GTS-301 (10−6 M) triggers only MAPK/ERK and PLCγ1 pathways. Thus, the identified features of attenuation of the morphine withdrawal syndrome in the rats under GTS-301 and GTS-302 effects could be associated with different activation pattern of the postreceptor pathways.

Anticancer Potential of Cyanidin and Cyanidin-3-Glucoside Through TrkB Receptor Inhibition: Evidence From Molecular Interaction Docking

Cancer remains a global health problem with persisten demand on therapeutic development to inhibit cancer cells growth without harmful effects on healthy cells. Plant bioactive compounds are intensively studied as anticancer via several signalling pathway. Anticancer therapy via inhibition of tropomyosin kinase receptor-B (TrkB) signal was previously proposed as target therapy. The role of plant metabolites cyanidin and cyanidin-3-glucoside as TrkB inhibitor is has not been investigated. This study was aimed to identify physicochemical of cyanidin and cyanidin- 3-glucoside as well as determine it’s role towards TrkB receptor signalling pathway through in silico approach. Molecular docking was performed using Hex 8.0.0 software and visualizes using Discovery Studio Visualizer. The energy binding of TrkB with cyanidin and cyanidin-3-glucoside was -263,21 kcal/mol and 281,65 kcal/mol respectively. Complex of cyanidin-3-glucoside had hydrogen and hydrophobic bond more than TrkB-cyanidin complex. The hydrogen bond formed at Lys637, Arg558 and Gly 561 amino residues. Physicochemical analysis demonstrated that both ligand are potential as kinase enzyme inhibitor. Cyanidin-3-glucoside was predicted more potential as anticancer than cyanidin via TrkB receptor inhibition. Future studies are required to confirm current finding both in-vitro and in-vivo models.

Dissection of signaling pathways regulating TrkB-dependent gephyrin clustering.

The TrkB receptor is known for its role in regulating excitatory neuronal plasticity. However, accumulating evidence over the past decade has highlighted the involvement of TrkB in regulating inhibitory synapse stability and plasticity, particularly through regulation of the inhibitory scaffold protein gephyrin, although with contradicting results. In this study, we extended on these findings by overexpressing rat TrkB mutants deficient in either Shc-or PLCγ-dependent signaling, as well as a kinase-dead mutant, to dissect the contributions of specific TrkB-dependent signaling pathways to gephyrin clustering. Our results demonstrate that TrkB signaling is required for gephyrin clustering on the perisomatic area of granule cells in the dentate gyrus in vivo. To further investigate, we expressed TrkB wild-type and mutants in hippocampal neurons in vitro. Under basal conditions, TrkB-Shc signaling was important for the reduction of gephyrin cluster size, while TrkB-PLCγ signaling accounts for gephyrin clustering specifically at synaptic sites. Concomitant, impaired PLCγ signaling was associated with disinhibition of transduced neurons. Moreover, chemically induced inhibitory long-term potentiation (chem iLTP) depended on TrkB signaling and the activation of both Shc and PLCγ pathways. Our findings suggest a complex, pathway-specific regulation of TrkB-dependent gephyrin clustering, both under basal conditions and during chem iLTP.

Deep brain stimulation mitigates memory deficits in a rodent model of traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments in attention and memory. Deep brain stimulation (DBS) is an established therapy for movement disorders that has been recently investigated for memory improvement in various disorders. In models of TBI, stimulation delivered to different brain targets has been administered to rodents long after the injury with the objective of treating motor deficits, coordination and memory impairment. ObjectiveTo test the hypothesis that DBS administered soon after TBI may prevent the development of memory deficits and exert neuroprotective effects. MethodsMale rats were implanted with DBS electrodes in the anterior nucleus of the thalamus (ANT) one week prior to lateral fluid percussion injury (FPI). Immediately after TBI, animals received active or sham stimulation for 6 h. Four days later, they were assessed in a novel object/novel location recognition test (NOR/NLR) and a Barnes maze paradigm. After the experiments, hippocampal cells were counted. Separate groups of animals were sacrificed at different timepoints after TBI to measure cytokines and brain derived neurotrophic factor (BDNF). In a second set of experiments, TBI-exposed animals receiving active or sham stimulation were injected with the tropomyosin receptor kinase B (TrkB) antagonist ANA-12, followed by behavioural testing. ResultsRats exposed to TBI given DBS had an improvement in several variables of the Barnes maze, but no significant improvements in NOR/NLR compared to Sham DBS TBI animals or non-implanted controls. Animals receiving stimulation had a significant increase in BDNF levels, as well as in hippocampal cell counts in the hilus, CA3 and CA1 regions. DBS failed to normalize the increased levels of TNFα and the proinflammatory cytokine IL1β in the perilesional cortex and the hippocampus of the TBI-exposed animals. Pharmacological experiments revealed that ANA-12 administered alongside DBS did not counter the memory improvement observed in ANT stimulated animals. ConclusionsDBS delivered immediately after TBI mitigated memory deficits, increased the expression of BDNF and the number of hippocampal cells in rats. Mechanisms for these effects were not related to an anti-inflammatory effect or mediated via TrkB receptors.

Small Molecule Compound DHPA Screened by Computer-Aided Drug Design and Molecular Dynamics Simulation Inhibits Neuroblastoma Cell Proliferation by Targeting TrkB.

Neuroblastoma (NB) is a rare and malignant pediatric solid tumor. Due to its heterogeneity, it poses significant challenges for treatment, resulting in a high mortality rate. This study aimed to identify new therapeutic drugs by modeling the TrkB receptor from PDB 4AT5 and conducting virtual screening of compounds from the YaTCM database (containing 47,696 compounds derived from 6220 Traditional Chinese Medicines). The screening utilized the E-pharmacophore approach to select compounds with potential binding affinity to TrkB. The binding abilities of these compounds were tested through molecular dynamics simulations, stretch dynamics simulations, and US simulations. Among the top 11 optimized hit compounds, DHPA and 3″-demethylhexahydrocurcumin are prominent. Further simulations reveal that they form stable receptor-ligand binary complexes with TrkB. In subsequent in vitro cell experiments, 3″-demethylhexahydrocurcumin is eliminated due to its high IC50 for killing NB cells. Low concentrations of DHPA can significantly kill NB cells. Additionally, DHPA can inhibit the expression of TrkB, the activation of TrkB's downstream signaling pathways, and affect the thermal stability of TrkB protein and its response to streptase protease degradation. DHPA may be a potential TrkB inhibitor.

A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice.

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

Brain-derived neurotrophic factor stimulates hypothalamic and gonadal reproductive hormones and oocyte maturation in zebrafish.

The brain-derived neurotrophic factor (BDNF) has been shown to regulate metabolism in zebrafish. This research shows that Bdnf is a regulator of female zebrafish reproduction and reproductive hormones. BDNF is a peptide widely known for its role in neurogenesis and synaptic plasticity. Its expression in non-neuronal tissues has been reported. In mammals, it is involved in ovarian development, follicle growth, oocyte maturation and early embryonic development. In zebrafish, it was demonstrated that Bdnf increases food intake and regulates metabolism. Reproduction and metabolism are tightly linked. We hypothesized that Bdnf modulates reproductive hormones and reproductive functions in zebrafish. This study aimed to determine Bdnf expression in the zebrafish reproductive axis and whether it modulates the reproductive endocrine milieu and oocyte biology in zebrafish. Our results show that bdnf and its receptor trkb and Bdnf-like immunoreactivity are present in zebrafish gonads and liver cells. This suggests Bdnf local production and possible actions within the gonads and liver. Intraperitoneal administration of 1, 10 or 100 ng/g body weight BDNF significantly (ANOVA, P < 0.05) increased sgnrh/cgnrh-II, kiss1 and cyp19a1b mRNAs in the zebrafish brain, steroidogenic enzymes (star and cyp19a1a) and key receptors in the zebrafish gonads. In vitro incubation of zebrafish liver cells with BDNF significantly (ANOVA, P < 0.05) increased estrogen receptor mRNAs and vitellogenin concentrations (ELISA) in the cells. BDNF (100 ng/mL) induced (ANOVA, P < 0.05) oocyte maturation in vitro at 24 h post-incubation and significantly upregulated cumulus-expansion-related genes (ANOVA, P < 0.05). Overall, our findings indicate a stimulatory role for Bdnf in the reproductive axis of zebrafish. This provides impetus for future research on its mechanism of action and potential practical applications to enhance reproduction in aquaculture.

Flavonoid chrysin activates both TrkB and FGFR1 receptors while upregulates their endogenous ligands such as brain derived neurotrophic factor to promote human neurogenesis.

Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) and plays a crucial role in neurological diseases. The process involves a series of steps, including NSC proliferation, migration and differentiation, which are regulated by multiple pathways such as neurotrophic Trk and fibroblast growth factor receptors (FGFR) signalling. Despite the discovery of numerous compounds capable of modulating individual stages of neurogenesis, it remains challenging to identify an agent that can regulate multiple cellular processes of neurogenesis. Here, through screening of bioactive compounds in dietary functional foods, we identified a flavonoid chrysin that not only enhanced the human NSCs proliferation but also facilitated neuronal differentiation and neurite outgrowth. Further mechanistic study revealed the effect of chrysin was attenuated by inhibition of neurotrophic tropomyosin receptor kinase-B (TrkB) receptor. Consistently, chrysin activated TrkB and downstream ERK1/2 and AKT. Intriguingly, we found that the effect of chrysin was also reduced by FGFR1 blockade. Moreover, extended treatment of chrysin enhanced levels of brain-derived neurotrophic factor, as well as FGF1 and FGF8. Finally, chrysin was found to promote neurogenesis in human cerebral organoids by increasing the organoid expansion and folding, which was also mediated by TrkB and FGFR1 signalling. To conclude, our study indicates that activating both TrkB and FGFR1 signalling could be a promising avenue for therapeutic interventions in neurological diseases, and chrysin appears to be a potential candidate for the development of such treatments.