TrkB Levels Research Articles

BDNF-TrkB/proBDNF-p75NTR pathway regulation by lipid emulsion rescues bupivacaine-induced central neurotoxicity in rats

Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic-ischemic neonatal rats.

Dexmedetomidine (DEX) has been reported to alleviate hypoxic-ischemic brain damage (HIBD) in neonates. This study aimed to investigate whether DEX improves cognitive impairment by promoting hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathway in neonatal rats with HIBD. HIBD was induced in postnatal day 7 rats using the Rice-Vannucci method, and DEX (25 μg/kg) was administered intraperitoneally immediately after the HIBD induction. The BDNF/TrkB/CREB pathway was regulated by administering the TrkB receptor antagonist ANA-12 through intraperitoneal injection or by delivering adeno-associated virus (AAV)-shRNA-BDNF via intrahippocampal injection. Western blot was performed to measure the levels of BDNF, TrkB, and CREB. Immunofluorescence staining was utilized to identify the polarization of astrocytes and evaluate the levels of neurogenesis in the dentate gyrus of the hippocampus. Nissl and TTC staining were performed to evaluate the extent of neuronal damage. The MWM test was conducted to evaluate spatial learning and memory ability. The levels of BDNF and neurogenesis exhibited a notable decrease in the hippocampus of neonatal rats after HIBD, as determined by RNA-sequencing technology. Our results demonstrated that treatment with DEX effectively increased the protein expression of BDNF and the phosphorylation of TrkB and CREB, promoting neurogenesis in the dentate gyrus of the hippocampus in neonatal rats with HIBD. Specifically, DEX treatment significantly augmented the expression of BDNF in hippocampal astrocytes, while decreasing the proportion of detrimental A1 astrocytes and increasing the proportion of beneficial A2 astrocytes in neonatal rats with HIBD. Furthermore, inhibiting the BDNF/TrkB/CREB pathway using either ANA-12 or AAV-shRNA-BDNF significantly counteracted the advantageous outcomes of DEX on hippocampal neurogenesis, neuronal survival, and cognitive improvement. DEX promoted neurogenesis in the hippocampus by activating the BDNF/TrkB/CREB pathway through the induction of polarization of A1 astrocytes toward A2 astrocytes, subsequently mitigating neuronal damage and cognitive impairment in neonates with HIBD.

TrkB inhibition of DJ-1 degradation promotes the growth and maintenance of cancer stem cell characteristics in hepatocellular carcinoma

Although TrkB may be associated with the pathogenesis of various cancer by upregulation, how upregulation of TrkB led to tumor progression in hepatocellular carcinoma (HCC) and the signaling mechanisms by which TrkB induces motility, invasion, metastasis, drug resistance, and acquisition of self-renewal traits has remained unclear. Here, we demonstrated that TrkB was significantly upregulated in highly metastatic HCC cells and HCC patients. Also, the increased TrkB levels were significantly correlated with tumor stages and poor survival of HCC patients. Furthermore, the upregulated TrkB expression enhances the metastatic ability of HCC cells through reduced anoikis sensitivity, induced migration, and colony formation. Most strikingly, TrkB markedly enhances the activation of STAT3 by preventing DJ-1 degradation through the formation of the TrkB/DJ-1 complex. This signaling mechanism is responsible for triggering cellular traits of highly aggressive HCC. The activation of the EMT program of HCC via increasing DJ-1 stability by TrkB induces the gain of cancer stem cell states and chemoresistance via the upregulation of stem cells cell markers and ABC transporters. Also, TrkB-mediated inhibition of DJ-1 degradation promotes tumor formation and metastasizes to other organs in vivo. Our observations illustrate that TrkB is a prognostic and therapeutic targeting in promoting aggressiveness and metastasis of HCC.

Exploration of the SIRT1-mediated BDNF-TrkB signaling pathway in the mechanism of brain damage and learning and memory effects of fluorosis.

Fluoride is considered an environmental pollutant that seriously affects organisms and ecosystems, and its harmfulness is a perpetual public health concern. The toxic effects of fluoride include organelle damage, oxidative stress, cell cycle destruction, inflammatory factor secretion, apoptosis induction, and synaptic nerve transmission destruction. To reveal the mechanism of fluorosis-induced brain damage, we analyzed the molecular mechanism and learning and memory function of the SIRT1-mediated BDNF-TrkB signaling pathway cascade reaction in fluorosis-induced brain damage through in vivo experiments. This study constructed rat models of drinking water fluorosis using 50 mg/L, 100 mg/L, and 150 mg/L fluoride, and observed the occurrence of dental fluorosis in the rats. Subsequently, we measured the fluoride content in rat blood, urine, and bones, and measured the rat learning and memory abilities. Furthermore, oxidative stress products, inflammatory factor levels, and acetylcholinesterase (AchE) and choline acetyltransferase (ChAT) activity were detected. The pathological structural changes to the rat bones and brain tissue were observed. The SIRT1, BDNF, TrkB, and apoptotic protein levels were determined using western blotting. All rats in the fluoride exposure groups exhibited dental fluorosis; decreased learning and memory abilities; and higher urinary fluoride, bone fluoride, blood fluoride, oxidative stress product, and inflammatory factor levels compared to the control group. The fluoride-exposed rat brain tissue had abnormal AchE and ChAT activity, sparsely arranged hippocampal neurons, blurred cell boundaries, significantly fewer astrocytes, and swollen cells. Furthermore, the nucleoli were absent from the fluoride-exposed rat brain tissue, which also contained folded neuron membranes, deformed mitochondria, absent cristae, vacuole formation, and pyknotic and hyperchromatic chromatin. The fluoride exposure groups had lower SIRT1, BDNF, and TrkB protein levels and higher apoptotic protein levels than the control group, which were closely related to the fluoride dose. The findings demonstrated that excessive fluoride caused brain damage and affected learning and memory abilities. Currently, there is no effective treatment method for the tissue damage caused by fluorosis. Therefore, the effective method for preventing and treating fluorosis damage is to control fluoride intake.

Elevated Plasma Levels of Mature Brain-Derived Neurotrophic Factor in Major Depressive Disorder Patients with Higher Suicidal Ideation.

Several pieces of evidence show that signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB), as well as inflammation, play a crucial part in the pathophysiology of depression. The purpose of our study was to evaluate plasma levels of BDNF-TrkB signaling, which are inflammatory factors in major depressive disorder (MDD) patients, and assess their associations with clinical performance. This study recruited a total sample of 83 MDD patients and 93 healthy controls (CON). All the participants were tested with the Hamilton Depression Scale (HAMD), the Beck Scale for Suicide Ideation, and the NEO Five-Factor Inventory. The plasma level of selected BDNF-TrkB signaling components (mature BDNF (mBDNF), precursor BDNF (proBDNF), tyrosine kinase B (TrkB), and tissue plasminogen activator (tPA)) and selected inflammatory factors (interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) were measured using an enzyme-linked immunosorbent assay (ELISA). Further, we performed correlation analysis to indicate the relationship between the plasma levels of the factors and clinical characteristics. Results: (i) A higher level of mBDNF and lower openness were observed in MDD patients with higher suicidal ideation than patients with lower suicidal ideation. (ii) In MDD patients, mBDNF was positively correlated with the sum score of the Beck Scale for Suicide Ideation (BSS). (iii) The levels of mBDNF, tPA, IL-1 β and IL-6 were significantly higher in all MDD subjects compared to the healthy controls, while the levels of TrkB and proBDNF were lower in MDD subjects. Conclusion: Our study provides novel insights regarding the potential role of mBDNF in the neurobiology of the association between depression and suicidal ideation and, in particular, the relationship between BDNF-TrkB signaling, inflammatory factors, and clinical characteristics in MDD.

Changes in Plasma TPH2, GDNF, Trk-b, BDNF, and proBDNF in People Who Died by Suicide.

Recent studies have shown that neuropeptides and neurotrophic factors may be involved in the pathophysiological mechanisms of suicide. However, the current research on this aspect is still insufficient. Our study aimed to explore the biological patterns of suicide deaths, including levels of BDNF, proBDNF, BDNF/proBDNF, Trk-b, GDNF, and TPH2. The researchers selected 25 normal control patients matched by age with 30 suicide deaths. We used enzyme-linked immunosorbent assays to detect the levels of BDNF, proBDNF, BDNF/proBDNF, Trk-b, GDNF, and TPH2 in the plasma of suicide and control subjects. proBDNF, BDNF/proBDNF, Trk-b, GDNF, and TPH2 levels are shown as the median (25th-75th percentile). BDNF levels are shown as the mean (standard error of the mean). (1) The levels of plasma TPH2 and proBDNF in people who died by suicide were significantly higher than those in the control group. (2) The plasma levels of GDNF and BDNF/proBDNF in the suicide group were obviously lower than those in the control group. (3) There was no significant difference in plasma BDNF or Trk-b concentrations between the suicide group and the control group.Plasma TPH2, GDNF, and proBDNF levels are related to suicide. Plasma neurotrophic factor markers may predict suicide risk.

Subchronic exposure to Tamoxifen modulates the hippocampal BDNF/ERK/Akt/CREB pathway and impairs memory in intact female rats

Tamoxifen (TAM), a Selective Estrogen Receptor Modulator (SERM), is commonly used to treat and prevent breast cancer. Memory impairment has been noticed in patients who experience hormone therapy in the case of TAM and other SERMs. Animal studies that mimic the TAM longer exposure effects are needed to better elucidate the adverse effects of continuous treatment in humans. This study evaluated the effects of TAM subchronic administration on the memory performance and hippocampal neural plasticity of intact female Wistar rats. Animals were treated intragastrically with TAM (0.25 and 2.5 mg/kg) for 59 days. The rats were subjected to the Object Location Test (OLT) and Object Recognition Test (ORT) to evaluate memory performance. After euthanasia, the hippocampus samples were excised and the protein levels of the BDNF/ERK/Akt/CREB pathway were evaluated. The rat's locomotor activity and hippocampal TrkB levels were similar among the experimental groups. TAM at both doses reduced the memory performance of female rats in the OLT and short-term memory of ORT, and impaired hippocampal levels of mBDNF, proBDNF, and pCREB/CREB. TAM only at the dose of 2.5 mg/kg reduced the memory performance of rats in the long-term memory of ORT and hippocampal pERK/ERK and pAkt/Akt ratios. TAM subchronic administration induced amnesic effects and modulated the hippocampal BDNF/ERK/Akt/CREB pathway in intact young adult female Wistar rats.

Transcranial direct current stimulation attenuates chronic pain in knee osteoarthritis by modulating BDNF/TrkB signaling in the descending pain modulation system

Knee osteoarthritis (KOA) is the most common cause of chronic pain, but its pain mechanisms are complex and may be closely related to the descending pain modulation system. Transcranial direct current stimulation (tDCS) is used for relieving pain, but its analgesic mechanisms are still being explored. The purpose of this study was to investigate the role of BDNF/TrkB signaling in chronic pain in KOA and to investigate whether this signaling is related to the analgesic effect of tDCS. Rats were injected with monosodium iodoacetate (MIA) into the left knee joint to establish a chronic pain model and then received 20 min of tDCS for 8 days. Rats were respectively administered the TrkB inhibitor ANA-12 after MIA modeling and exogenous BDNF after tDCS treatment. Behaviors testing was assessed by hot plate and von Frey hairs using the up-down method. In addition, the expression levels of BDNF and TrkB on the periaqueductal gray (PAG)-the rostral ventromedial medulla (RVM)-the spinal dorsal horn (SDH) axis were detected by Western blot and Immunohistochemistry staining. Behavioral results show that tDCS treatment and ANA-12 injection reversed MIA-induced allodynia while reducing BDNF and TrkB expression levels. Furthermore, injection of exogenous BDNF reversed the therapeutic effect of tDCS on pain. These results indicate that upregulation of the BDNF/TrkB signaling in the descending pain modulation system may play an important role in KOA-induced chronic pain in rats, and tDCS may reduce KOA-induced chronic pain by inhibiting the BDNF/TrkB signaling in the descending pain modulation system.

Effects of Tail Pinch on BDNF and trkB Expression in the Hippocampus of Roman Low- (RLA) and High-Avoidance (RHA) Rats.

In this article, we describe the effects of tail pinch (TP), a mild acute stressor, on the levels of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor B (trkB) proteins in the hippocampus (HC) of the outbred Roman High- (RHA) and Low-Avoidance (RLA) rats, one of the most validated genetic models for the study of fear/anxiety- and stress-related behaviors. Using Western blot (WB) and immunohistochemistry assays, we show for the first time that TP induces distinct changes in the levels of BDNF and trkB proteins in the dorsal (dHC) and ventral (vHC) HC of RHA and RLA rats. The WB assays showed that TP increases BDNF and trkB levels in the dHC of both lines but induces opposite changes in the vHC, decreasing BDNF levels in RHA rats and trkB levels in RLA rats. These results suggest that TP may enhance plastic events in the dHC and hinder them in the vHC. Immunohistochemical assays, carried out in parallel to assess the location of changes revealed by the WB, showed that, in the dHC, TP increases BDNF-like immunoreactivity (LI) in the CA2 sector of the Ammon's horn of both Roman lines and in the CA3 sector of the Ammon's horn of RLA rats while, in the dentate gyrus (DG), TP increases trkB-LI in RHA rats. In contrast, in the vHC, TP elicits only a few changes, represented by decreases of BDNF- and trkB-LI in the CA1 sector of the Ammon's horn of RHA rats. These results support the view that the genotypic/phenotypic features of the experimental subjects influence the effects of an acute stressor, even as mild as TP, on the basal BDNF/trkB signaling, leading to different changes in the dorsal and ventral subdivisions of the HC.

Brain-Derived Neurotrophic Factor (BDNF) in Mechanisms of Autistic-like Behavior in BTBR Mice: Crosstalk with the Dopaminergic Brain System.

Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus-mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF-DA crosstalk in the autistic-like phenotype of BTBR mice.

Music with Different Tones Affects the Development of Brain Nerves in Mice in Early Life through BDNF and Its Downstream Pathways.

As a means of environmental enrichment, music environment has positive and beneficial effects on biological neural development. Kunming white mice (61 days old) were randomly divided into the control group (group C), the group of D-tone (group D), the group of A-tone (group A) and the group of G-tone (group G). They were given different tonal music stimulation (group A) for 14 consecutive days (2 h/day) to study the effects of tonal music on the neural development of the hippocampus and prefrontal cortex of mice in early life and its molecular mechanisms. The results showed that the number of neurons in the hippocampus and prefrontal cortex of mice increased, with the cell morphology relatively intact. In addition, the number of dendritic spines and the number of dendritic spines per unit length were significantly higher than those in group C, and the expressions of synaptic plasticity proteins (SYP and PSD95) were also significantly elevated over those in group C. Compared with group C, the expression levels of BDNF, TRKB, CREB, PI3K, AKT, GS3Kβ, PLCγ1, PKC, DAG, ERK and MAPK genes and proteins in the hippocampus and prefrontal cortex of mice in the music groups were up-regulated, suggesting that different tones of music could regulate neural development through BDNF and its downstream pathways. The enrichment environment of D-tone music is the most suitable tone for promoting the development of brain nerves in early-life mice. Our study provides a basis for screening the optimal tone of neuroplasticity in early-life mice and for the treatment of neurobiology and neurodegenerative diseases.

Brain-derived neurotrophic factor promotes airway smooth muscle cell proliferation in asthma through regulation of transient receptor potential channel-mediated autophagy

ObjectiveIncreased proliferation of airway smooth muscle cells (ASMCs) is a key feature of airway remodeling in asthma. This study aims to determine whether brain-derived neurotrophic factor (BDNF) regulates ASMC proliferation and airway remodeling via the transient receptor potential channels (TRPCs)/autophagy axis. MethodsHuman ASMCs were isolated and passively sensitized with human asthmatic serum. Protein levels of BDNF and its receptor TrkB, TRPC1/3/6, autophagy markers, intracellular Ca2+ concentration ([Ca2+]i), LC3 immunofluorescence, cell proliferation, cell cycle population were examined. Wistar rats were sensitized with OVA to establish asthma models. ResultsIn asthmatic serum-sensitized human ASMCs, BDNF overexpression or recombinant BDNF (rhBDNF) increased TrkB/TRPC1/3/6 axis, [Ca2+]i, autophagy level, cell proliferation, cell number in the S+G2/M phase and decreased cell number in the G0/G1 phase, whereas BDNF knockdown exerted the opposite effects. Furthermore, TRPC channel blocker SKF96365 and TRPC1/3/6 knockdown reversed the effects of the rhBDNF-mediated induction of [Ca2+]i, autophagy level, cell proliferation and cell number in the S+G2/M phase. Moreover, the autophagy inhibitor (3-MA) rescued the rhBDNF-mediated induction of cell proliferation and cell number in the S+G2/M phase. Further in vivo assays revealed that BDNF altered the pathology of airway remodeling, promoted the infiltration of inflammatory cells, promoted the proliferation of ASMCs, and upregulated the protein levels of TrkB, TRPC1/3/6, and autophagy markers in asthma model rats. ConclusionWe conclude that BDNF promotes ASMCs proliferation in asthma through TRPC-mediated autophagy induction.

Lamina-specific association between reduced mRNA levels of tyrosine kinase b and glutamate decarboxylase 67 in the orbitofrontal cortex in bipolar disorder: A possible reflective of defective connectivity in bipolar disorder

IntroductionLamina-specific alterations of inhibitory circuitries have been considered the crucial pathogenesis of perceptual, cognitive and behavioral symptoms presented in schizophrenia and mood disorders. Especially, with emerging evidences indicating the close lamina-specific relationship between synaptic defects and γ-Aminobutyric acid (GABA)-related gene dysfunctions, it has been suggested the mRNA dysregulations of Tyrosine kinase B (TrkB) and Glutamate decarboxylase 67 (GAD67) could particularly be implicated in middle and deep layers of neocortex of patients with major psychiatric disorders.ObjectivesGiving inquiries of whether defects of these mRNA levels in Orbitofrontal cortex (OFC) would be involved as lamina-specific patterns in individuals with schizophrenia and mood disorders.MethodsWe examined mRNA levels of BDNF, TrkB and GAD67 in each OFC layer I through VI. We analyzed data from postmortem brain tissue of the Stanley Neuropathology Consortium Integrative Database (SNCID). SNCID consists of 15 subjects in each of four groups (schizophrenia, bipolar disorder, major depression without psychotic features, and unaffected controls). All groups were matched for age, sex, race, brain pH and post-mortem interval.ResultsWe found TrkB mRNA levels to be significantly reduced in layer VI in both groups with schizophrenia (25.8%) and bipolar disorder (35.7%) compared with controls. GAD67 mRNA levels were also significantly reduced in layer III and IV in patients with schizophrenia (23.4% and 22.7%, respectively) and bipolar disorder (31.2% and 24.9%, respectively) compared with controls. Individuals with major depression showed only trends toward decreased mRNA levels of GAD67 in layer III and IV and of TrkB in layer VI compared with controls. TrkB mRNA levels in layer VI were significantly correlated with GAD67 mRNA levels in layer III (ρ=0.581, p=0.037) and IV (ρ=0.857, p<0.001) in subjects with bipolar disorder, but not in those with schizophrenia. When analyzed with partial correlation controlling the effects of pH and PMI, significance of correlation remained only between GAD67 mRNA in layer IV and TrkB mRNA in layer VI in individuals with bipolar disorder (ρ=0.768, p=0.006).ConclusionsThe resulting lamina-specific decreases in inhibitory tone across layers of OFC may contribute to the unrestrained irritability and violent behaviors in common shared by both patients with schizophrenia and bipolar disorder. Nonetheless, our findings indicate the obvious correlations between lamina-specifically altered TrkB and GAD67 mRNA levels in OFC might be a candidate for endophenotype of bipolar disorder.Disclosure of InterestNone Declared

Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling.

Liver fibrosis is a leading indicator for increased mortality and long-term comorbidity in NASH. Activation of HSCs and excessive extracellular matrix production are the hallmarks of liver fibrogenesis. Tyrosine kinase receptor (TrkB) is a multifunctional receptor that participates in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, the regulatory network and therapeutic potential of TrkB were explored in the progression of hepatic fibrosis. The protein level of TrkB was decreased in mouse models of CDAHFD feeding or carbon tetrachloride-induced hepatic fibrosis. TrkB suppressed TGF-β-stimulated proliferation and activation of HSCs in 3-dimensional liver spheroids and significantly repressed TGF-β/SMAD signaling pathway either in HSCs or in hepatocytes. The cytokine, TGF-β, boosted Nedd4 family interacting protein-1 (Ndfip1) expression, promoting the ubiquitination and degradation of TrkB through E3 ligase Nedd4-2. Moreover, carbon tetrachloride intoxication-induced hepatic fibrosis in mouse models was reduced by adeno-associated virus vector serotype 6 (AAV6)-mediated TrkB overexpression in HSCs. In addition, in murine models of CDAHFD feeding and Gubra-Amylin NASH (GAN), fibrogenesis was reduced by adeno-associated virus vector serotype 8 (AAV8)-mediated TrkB overexpression in hepatocytes. TGF-β stimulated TrkB degradation through E3 ligase Nedd4-2 in HSCs. TrkB overexpression inhibited the activation of TGF-β/SMAD signaling and alleviated the hepatic fibrosis both in vitro and in vivo . These findings demonstrate that TrkB could be a significant suppressor of hepatic fibrosis and confer a potential therapeutic target in hepatic fibrosis.

Exposure to enriched environment ameliorated chronic unpredictable mild stress-induced depression-like symptoms in rats via regulating the miR-92a-3p/kruppel-like factor 2 (KLF2) pathway

BackgroundSilencing of miR-92a-3p may be beneficial in relieving depression of chronically stressed rats. The level of kruppel-like factor 2 (KLF2) was increased in the striatum of depressed rats after ketamine treatment. Enriched environment (EE) ameliorated depression-like behaviors in rats. However, the specific mechanism of EE treatment on depression induced by chronic unpredictable mild stress (CUMS) remains unclear. MethodsAfter CUMS-induced male Sprague Dawley rats were treated under EE or/and Adeno-Associated Virus (AAV)-miR-92a-3p, depression-like behaviors, cognitive ability, dendritic spine density, as well as levels of miR-92a-3p and KLF2 were detected by the behavioral tests, morris water maze test, Golgi staining, and quantitative real-time polymerase chain reaction (qRT-PCR) as needed. The body weight of rats was also measured. Next, primary hippocampal neurons were cultivated. The targeting relationship between miR-92a-3p and KLF2 was analyzed by TargetScan v7.2 and dual-luciferase reporter assay. After hippocampal neurons were transfected with miR-92a-3p mimic or/and overexpressed KLF2 vector, the cell viability, and apoptosis, together with the levels of KLF2, brain-derived neurotrophic factor (BDNF), phosphorylated (p)-tropomysin related kinase B (p-TrkB) and TrkB were determined by MTT assay, flow cytometry, qRT-PCR, and western blot as needed. ResultsEE ameliorated CUMS-induced depression-like behaviors and cognitive ability, and elevated the neuronal dendritic spine density and KLF2 level, but reduced miR-92a-3p level in hippocampal tissues, while the above effects were reversed by AAV-miR-92a-3p. MiR-92a-3p mimic restrained cell viability, along with p-TrkB/ TrkB and BDNF levels, but promoted apoptosis in hippocampal neurons, which were reversed by overexpressed KLF2. ConclusionEE ameliorates CUMS-induced depression-like symptoms in rats via regulating the miR-92a-3p/KLF2 pathway.

Relationship between serum brain-derived neurotrophic factor and cognitive impairment in children with sleep-disordered breathing.

As an important neuroprotective factor, the brain-derived neurotrophic factor (BDNF) may have a key role in cognitive impairment in children with sleep-disordered breathing (SDB). The main aim of this study was to compare the levels of BDNF and tyrosine kinase receptor B (TrkB) in normal children and those with obstructive sleep apnea (OSA) and primary snoring (PS) and to explore a possible link between BDNF/TrkB, inflammation, and SDB with cognitive impairment in children. A total of 44 OSA children and 35 PS children who completed polysomnography between October 2017 and October 2019 were enrolled. At the same time, 40 healthy children during the same period were included as a control. Enzyme-linked immunosorbent assay was used to measure serum indices of BDNF, TrkB, interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). Correlation and pooled analyses were performed between the cognitive scores and four serological indicators. Logistic regression was used to analyze the risk factors for cognitive impairment. Significant differences were found in serum BDNF, TrkB, IL-1β, and TNF-α between the three groups (all P < 0.01). The serum BDNF and TrkB in the OSA and PS groups were lower than those in the control group, whereas the serum IL-1β and TNF-α were higher than those in the control group (all P < 0.05). Moreover, among these four indices, the strongest correlation was found between BDNF and the Chinese Wechsler Intelligence Scale (all P < 0.05). Logistic regression analysis revealed a correlation between OSA status, TrkB, and course of mouth breathing and cognitive status. The levels of serum BDNF and TrkB were related to cognitive impairment in children with SDB. Also, BDNF and TrkB could be used as noninvasive and objective candidate markers and predictive indices of cognitive impairment in children with SDB.

Bone Marrow Mesenchymal Stem Cells (BMSC) Homing with Chemotaxis Transplantation of Stromal Cell-Derived Factor 1a Promotes the Corneal Damage Repair

This study analyzed the effect of bone marrow mesenchymal stem cells (BMSC) homing with chemotaxis transplantation of SDF-1a on the repair of corneal damage. The SDF-1a with varied concentration was added. They were divided into A group, B group, C group, D group and control group followed by analysis of corneal cell survival by MTT, apoptosis by flow cytometry, and Trkb level by immunohistochemical staining. There was an increasing tendency on the quantity of chemotactic cells (P &lt;0.05) with a highest quantity in C group. The recruitment of BMSC could be prompted by SDF-1a and the chemotactic effect was the best when SDF-1a concentration was 100 ng/ml. The survival rate and Trkb protein level in experimental groups was higher than that in control group with highest survival rate and Trkb level in C group. In conclusion, corneal injury repair is prompted by BMSC homing with chemotaxis transplantation of SDF-1a, indicating that it might be used as a novel approach to promote corneal injury repair.

Chemical component analysis of the traditional Chinese medicine Guipi Tang and its effects on major depressive disorder at molecular level

Ethnopharmacological relevanceGuipi Tang (GPT) is a widely used traditional Chinese medicine that is used to treat major depressive disorder. However, the molecular mechanisms of its effects remain unclear. Aim of the studyThis study aimed to investigate the antidepressant-like effects of GPT and explore its underlying molecular mechanisms. Materials and methodsMale Sprague–Dawley rats were subjected to a chronic unpredictable mild stress (CUMS) procedure and treated with various doses of GPT, with fluoxetine treatment as a positive control. Behavioural tests (including sucrose preference test, novelty-suppressed feeding test, open-field test and forced swim test), terminal deoxynucleotidyl transferase dUTP nick end labeling and enzyme-linked immunosorbent assay were conducted. The levels of Bax, Bcl-2, cleaved caspase-3, PI3K, p-PI3K, AKT, p-AKT, BDNF, TrkB and CREB or p-CREB were assessed at the protein level using western blotting or immunofluorescence. ResultsGPT consists of mainly known drugs, such as liquiritin and ginsenosides. It reversed depressive behaviours and decreased cell apoptosis in the hippocampi of CUMS rats. It significantly upregulated the protein level of Bax, p-Akt, p-PI3K, BDNF, TrkB and p-CREB and downregulated the level of cleaved caspase-3 and Bcl-2. ConclusionsGPT had anti-depressive activity as indicated by the amelioration of depression-like behaviour and the inhibition of hippocampal neuronal apoptosis in CUMS rats. This inhibition was mediated partly by modulating the PI3K/Akt and/or BDNF/TrkB/CREB pathway, in which, glycosides, the main components of GPT, might be involved.

Effects of neuronavigation-guided rTMS on serum BDNF, TrkB and VGF levels in depressive patients with suicidal ideation

BackgroundNeuronavigation-guided high-dose repetitive transcranial magnetic stimulation (rTMS) could rapidly treat depressive patients with suicidal ideation. But the mechanism of rTMS still needs to be elucidated. This study aims to investigate if rTMS improves suicidal ideation and depressive symptoms by influencing brain-derived neurotrophic factor (BDNF), tropomysin receptor kinase B (TrkB) and VGF levels. MethodsIn the present 1-week study, 59 treatment-naive depressive patients with suicidal ideation were randomly assigned to the active (n = 31) or sham (n = 28) rTMS group. The severity of suicidal ideation and depression were measured by the Beck Scale for Suicide Ideation, the Hamilton Depression Rating Scale and Montgomery–Asberg Depression Rating Scale. Fasting venous blood samples were collected at baseline and after treatment. Serum protein concentrations of BDNF, TrkB and VGF were measured by enzyme linked immunosorbent assay. ResultsWe found after treatment the levels of BDNF in the active rTMS group were higher than the sham group (p = 0.011), TrkB levels were decreased in the active group (p < 0.001), VGF levels were increased in the active group (p = 0.005). Post-treatment VGF levels in the active group were higher than the sham group (p = 0.008). However, there were no significant correlation between changes in BDNF, TrkB and VGF levels and the changes in clinical variables. LimitationsParticipants taking medication may affect the results. ConclusionsOur results suggest that the BDNF-TrkB pathway and VGF may be implicated in the mechanisms underlying neuronavigation-guided rTMS for treating depressive patients with suicidal ideation.

Trifluoro-icaritin ameliorates spared nerve injury-induced neuropathic pain by inhibiting microglial activation through α7nAChR-mediated blockade of BDNF/TrkB/KCC2 signaling in the spinal cord of rats

Neuropathic pain is still a serious and unsolved health problem. Activation of α7 nicotinic acetylcholine receptor (α7nAChR) is known to modulate neuropathic pain by inhibiting microglial activation and BDNF/TrkB/KCC2 signaling. We previously identified that trifluoro-icaritin (ICTF) has an attenuated effect on spared nerve injury (SNI)-induced neuropathic pain, but its potential mechanisms remain unknown. Here, the pain-related behaviors were determined by paw withdrawal threshold (PWT), CatWalk gait analysis, rotarod test, open field test and elevated plus maze test. The expression of pain-related signal molecules was evaluated by Western blot and immunofluorescence staining. The results showed that ICTF (5.0 mg/kg, i.p.) successfully relieved SNI-induced mechanical allodynia and anxiety-like behavior, we subsequently found there existed either positive or negative correlation between mechanical allodynia and gait parameters or rotating speed following ICTF treatment. Moreover, ICTF not only enhanced the expression of spinal α7nAChR, KCC2, CD206 and IL-10, but also decreased the levels of spinal BDNF, TrkB, CD11b, Iba-1, CD40 and IL-1β in SNI rats. Conversely, α7nAChR antagonist α-Bgtx (I.T.) effectively reversed the inhibitory effects of ICTF on SNI rats, resulting in a remarkable improvement of mechanical allodynia, activation of microglia. and suppression of α7nAChR-mediated BDNF/TrkB/KCC2 signaling. Additionally, exogenous BDNF (I.T.) dramatically abrogated both blockade of BDNF/TrkB/KCC2 cascade and alleviation of mechanical allodynia by ICTF treatment. Altogether, the study highlighted that ICTF could relieve SNI-induced neuropathic pain by suppressing microglial activation via α7nAChR-mediated inhibition of BDNF/TrkB/KCC2 signaling in the spinal cord, suggesting that ICTF may be served as a possible painkiller against neuropathic pain.