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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.

Current antiepileptic drugs are effective in suppressing motor seizures; however, they often do not address the underlying factors such as oxidative stress, inflammation, and neurotrophic imbalances that contribute to the development of epilepsy. Recently, flavonoids sourced from diet have attracted attention as neuromodulators that can target these root causes. This study evaluated the protective effects of sakuranetin—a flavonoid found in edible Prunus species—against pentylenetetrazole (PTZ)-induced seizures and neurochemical changes in mice. Swiss albino mice ( n  = 6/group) were treated with saline, PTZ (35 mg/kg, intraperitoneally), or PTZ combined with sakuranetin (10 or 20 mg/kg, orally) every other day for 28 days. The study assessed seizure activity, oxidative stress markers, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and caspase-3 activity. Additionally, in silico docking and 100 ns molecular dynamics simulations were performed to investigate sakuranetin’s interactions with BDNF, TrkB, and D₂-like receptors. The results showed that sakuranetin treatment significantly improved seizure parameters. The onset latency was extended with both doses. The duration of clonic–tonic seizures was reduced by half, and mortality rates dropped from 50% to 8%. PTZ-induced reductions in neurotransmitters (such as GABA, dopamine, norepinephrine, serotonin, and acetylcholine) were restored, antioxidant defenses (including superoxide dismutase, catalase, and glutathione) were enhanced, and both lipid peroxidation (measured by malondialdehyde) and nitrosative stress (nitric oxide) were significantly decreased. Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were reduced, BDNF and TrkB levels approached control levels, and caspase-3 activity was diminished. Docking studies and MM-GBSA analyses indicated that BDNF was the most favorable binding partner for sakuranetin (with a binding free energy of approximately − 57 kcal/mol), and the simulations affirmed the stability of the complex. These findings suggest that sakuranetin has substantial, multi-target anticonvulsant effects by restoring neurotransmitter balance, enhancing antioxidant capacity, suppressing neuroinflammation, and revitalizing BDNF/TrkB signaling. Given its dietary origin, sakuranetin warrants further investigation as a potential nutraceutical candidate for managing epilepsy.

Depression has increasingly become a disease that seriously harms people’s mental health around the world. Icariin is the main active component of Epimedii Herba and effective on protecting the central nervous system. The purpose of this study was to explore the mechanism of icariin against depression based on network pharmacology and molecular docking. The potential targets related to icariin and depression were obtained by accessing network databases. The Metascape database was used for the enrichment analysis of GO function and KEGG pathways. A common target-pathway network was constructed using Cytoscape 3.9.0 software. Schr ö dinger Maestro 12.8 was adopted to evaluate the binding ability of icariin to core targets. Mice were induced by the chronic unpredictable mild stress (CUMS) model, and the prediction results of this study were verified by in vivo experiments. A total of 109 and 3294 targets were identified in icariin and depression, respectively. The common target-pathway network was constructed, and 7 core target genes were obtained. The molecular docking results of the 7 core target genes with icariin showed good affinity. In a CUMS-induced depression model, we found that icariin could effectively improve depression-like behavior of mice, increase the expression of monoamine neurotransmitters 5-hydroxytryptamine, dopamine, and norepinephrine, decrease the secretion of inflammatory factors tumor necrosis factor-α, interleukin-6, and interleukin-1β, and upregulate the relative expression levels of BDNF, p-TrkB/TrkB, p-Akt/Akt, p-CREB/CREB, MAPK3, MAPK1, Bcl-2, EGFR, and mTOR. The results suggest that icariin has certain antidepressant effects, and may be mediated by the BDNF-TrkB signaling pathway. It provides new ideas for the treatment of depression in the future.

Tyrosine Kinase beta (TRKβ), is a type I membrane receptor which plays a major role in various signalling pathways. TRKβ was found to be upregulated in various cancers and contrastingly downregulated in various neurodegenerative disorders. Hitherto, contemporary drug research is oriented towards discovery of TRKβ inhibitors, thus neglecting the development of TRKβ agonists. This research is aimed at identifying FDA approved drugs exhibiting repurposable potential as TRKβ agonists by mapping them with fingerprints of the BDNF/TRKβ interaction interface. Initially, crucial interacting residues were retrieved and a receptor grid was generated around it. TRKβ agonists were retrieved from literature search and a drug library was created for each agonist based on its structural and side effect similarities. Subsequently, molecular docking and dynamics were performed for each library to identify the drugs possessing affinity towards the binding pocket of TRKβ. The study revealed molecular interactions of Perospirone, Droperidol, Urapidil, and Clobenzorex with the crucial amino acids lining the active binding pocket of TRKβ. Subsequent network pharmacological analysis of the above drugs revealed their interactions with key proteins involved in neurotransmitter signalling pathways. Clobenzorex displayed high stability in dynamics simulation and therefore this drug is recommended for further experimental evaluations to attain better mechanistic insights and predict its implications in correcting neuropathological aberrations. This study's focus on the interaction interface between TRKβ and BDNF, combined with the utilization of fingerprint analysis for drug repurposing, contributes to our understanding of neurotrophic signalling and holds potential for identifying new therapeutic options for neurological disorders.

7,8-dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.

Hesperidin (3,5,7-trihydroxyflavanone 7-rhamnoglucoside) is a β-7-rutinoside of hesperetin (4′-methoxy-3′,5,7-trihydroxyflavanone), abundantly found in citrus fruits and known to interact with various cellular pathways to show a variety of pharmacological effects. The present study was envisaged to understand the anticonvulsant effect of hesperidin in a zebrafish model of pentylenetetrazole (PTZ)-induced convulsions, with the support of in silico docking. Healthy zebrafish larvae were preincubated with hesperidin (1, 5, and 10 µM) for 1 h, before PTZ exposure. Hesperidin treatment significantly increased the seizure latency and minimized PTZ-induced hyperactive responses. A significant reduction in c-fos expression further supported the suppression of neuronal excitation following hesperidin incubation in the larvae exposed to PTZ. The treatment also modulated larval bdnf expression and reduced the expression of il-10 . The results of in vivo studies were further supported by in silico docking analysis, which showed the affinity of hesperidin for the N-methyl- d -aspartate receptor, the gamma-aminobutyric acid receptor, Interleukin 10 and the TrkB receptor of brain-derived neurotrophic factor. The results concluded that hesperidin suppresses PTZ-mediated seizure in zebrafish larvae through interaction with the central CREB–BDNF pathway.

   The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC 50 : 17.500 ± 0.267 μg/mL) compared to ascorbic acid (IC 50 : 38.858 ± 0.263 μg/mL) and curcumin (27.189 ± 0.192 μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28 days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test ( P  < 0.001) and significantly reduced the immobility period in the tail suspension test ( P  < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of 5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant. Graphical Abstract

Objective Xiao‐Chai‐Hu‐Tang (XCHT) has been demonstrated to exert an antidepressant effect during long‐term clinical practices. However, the potential mechanisms of XCHT remain unknown. This study aims to investigate the effect of XCHT on chronic unpredictable mild stress‐induced mice with depressive‐like behaviors and to explore the underlying mechanisms. Methods The active compositions and potential related targets of XCHT in the brain were obtained through UPLC‐Q‐TOF‐MS, network pharmacology, and bioinformatics analyses, verified by experimental validation. Then, the protein–protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and molecular docking were used to predict the core targets and mechanisms of XCHT on depression. After being treated with XCHT standard decoction, based on enzyme‐linked immunosorbent assay (ELISA), non‐targeted metabolism, targeted LC–MS analyses, RNA‐seq, quantitative RT‐PCR, immunofluorescence, and western blotting were determined to clarify the mechanism of XCHT in the treatment of anxiety and depression disorder. Results In total, 166 active ingredients and 525 related targets of XCHT were detected and selected from the network databases. The inflammatory response and metabolism of neurotransmitters were the main related signaling pathways predicted by KEGG enrichment analyses. Behavioral testing shows that XCHT has antidepressant effects, and untargeted metabolomic studies showed it significantly reduced levels of the neurotoxic substance quinoline acid. Combining the results of molecular docking, RNA‐seq, and western blot revealed that XCHT regulated nerve regeneration via BDNF/TrkB/CREB and PI3K/AKT signaling pathways. Immunofluorescence analysis revealed that XCHT downregulated the chronic stress‐induced activation of microglia and astrocytes in the hippocampus. Conclusion XCHT exerts antidepressant functions by modulating neuroinflammation and neuroregeneration. XCHT alleviates depression by anti‐neuroinflammation and rebalancing the HPA axis, neurotransmitter release, and tryptophan metabolic pathway. Meanwhile, XCHT promotes neurogenesis by up‐regulating the BDNF/PI3K/AKT signaling pathway, resulting in harmonizing the neuroendocrine network.

Background Bromelain is a mixture of protease enzyme extract from the fruit or stem of the pineapple plant. It has a wide range of biological actions, and it is most commonly used as an anti-inflammatory agent. This study was designed to investigate the antidepressant effect of bromelain on chronic unpredictable stress (CUS)-induced depression in rat models by targeting various molecular mechanisms. Result We studied the in silico analysis of the antidepressant potential of bromelain by docking with various proteins involved in the pathophysiology of depression. As a result of in silico studies, bromelain showed good binding energy with IL1β, 5-HT, BDNF, CREB, and TrkB. The mRNA expression of BDNF, TrkB, AKT, ERK, and IL-1β was studied by qRT-PCR. Gene expression studies showed a significant decrease in BDNF, TrkB, AKT, and ERK in chronic unpredictable stress, whereas there was a significant increase in the case of the bromelain- and fluoxetine-treated group. Since neuroinflammation is also one of the major concerns in the pathophysiology of depression, pro-inflammatory cytokines were also studied along with apoptotic markers using ELISA. ELISA results showed a significant increase in inflammatory cytokines in CUS, and it was significantly decreased in the case of the bromelain- and fluoxetine-treated group. Similarly, there was an increased concentration of pro-apoptotic protein in the CUS group, whereas it was decreased in the bromelain and fluoxetine groups. Conclusions From the results, it is clear that bromelain exerts an antidepressive effect by preventing neuroinflammation and neurodegeneration and by enhancing neurogenesis and neuroplasticity. Graphical abstract

Background Compulsive relapse (reinstatement) behavior of methamphetamine underlies the difficulty of withdrawal and is associated with abnormal BDNF‐mediated synaptic plasticity. However, how to intervene in this aberrant synaptic plasticity to prevent its reinstatement behavior in mice has not fully been studied. Methods The CPP was used to establish a model of methamphetamine‐induced reinstatement behavior in C57BL/6 mice. Intraperitoneal injections of TEN were administered during the remission phase after the successful establishment of the CPP model to investigate the therapeutic effects on reinstatement. Immunofluorescence experiments were used to detect c‐fos expression in hippocampal CA1 neurons. Electrophysiological methods were used to determine glutamatergic transmission in hippocampal CA1 neural circuits. Western blotting was used to detect BDNF/TrKB and PSD‐95 protein expressions. Molecular docking was used to predict TEN molecule–protein binding. Results Compared with control mice, METH‐treated mice presented increased CPP scores during the reinstatement phase, whereas, compared to METH‐treated mice, TEN‐treated mice presented significantly lower CPP scores. Immunofluorescence experiments indicated that TEN was able to inhibit the METH‐induced increase in c‐fos content. In addition, we found that TEN alleviates the METH‐triggered increase in glutamatergic transmission in mouse hippocampal CA1 neurons. Importantly, molecular docking studies demonstrated that TEN binds with BDNF, which may be important targets for its biological function. We also demonstrated that interfering with BDNF inhibits the therapeutic effect of TEN on the reinstatement of METH addiction. Conclusion Our findings suggest that TEN treats METH‐induced reinstatement behavior by binding to BDNF, which may provide a novel target for treating relapse in patients addicted to METH. Tenuifolin attenuates methamphetamine‐induced reinstatement in mice by regulating hippocampal postsynaptic BDNF signaling. Left, The reduction of the expression of BDNF and PSD‐95 levels and abnormal synaptic plasticity promote METH‐induced reinstatement behavior in mice. Right, TEN treatment increases the expression of BDNF and PSD 95 and improves the function of synaptic plasticity to decrease METH‐induced reinstatement behavior.