Search Results (47)

Brain-derived neurotrophic factor (BDNF) is critical for neuronal survival. Amyloid-β monomers (Aβ42M) and oligomers (Aβ42O) have trophic and toxic effects on neuronal survival, respectively. Branched oligosaccharides (BOs) and catechins (CAs) can specifically bind to Aβ42M/Aβ42O, influencing both effects. However, whether and how Aβ42M/Aβ42O influences BDNF remains unknown. This study investigated the interaction between Aβ42M/Aβ42O and BDNF, the effects of Aβ42M and Aβ42O on BDNF binding to the TrkB/p75 receptor and their impact on BDNF-supported cell survival, and the roles of BOs and CAs in these processes. BDNF exhibited stronger binding affinity for Aβ42M and Aβ42O than BOs/CAs. Aβ42M increased neuronal viability by synergistically enhancing BDNF binding to TrkB and p75, whereas Aβ42O decreased neuronal viability by inactivating/consuming BDNF, thereby reducing its binding to these receptors. BDNF-Aβ42O binding appeared to mutually neutralize/counteract each other’s biological effects; therefore, increasing BDNF levels might reduce Aβ42O’s neurotoxicity. By competitively targeting Aβ42M/Aβ42O rather than BDNF or its receptors, BOs and CAs enhanced these effects. These findings suggest that Aβ42M’s neurotrophicity was directly linked to its synergistic enhancement of BDNF activity, whereas Aβ42O’s neurotoxicity was primarily due to its inactivation or consumption of BDNF. This study provided valuable insights for developing BOs/CAs-based neuroprotective therapeutics or nanomaterials against AD. Full article

Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system’s (CNS’s) neurons. BDNF binds to TrkB (a tyrosine kinase) with high affinity, and the resulting downstream intracellular signaling cascades play crucial roles in determining cell fate, including neuronal differentiation and maturation of the CNS neurons. It has been well demonstrated that the downregulation/dysregulation of the BDNF/TrkB system is implicated in the pathogenesis of neurologic and psychiatric disorders, such as Alzheimer’s disease (AD) and depression. Interestingly, the effects of BDNF mimetic compounds including flavonoids, small molecules which can activate TrkB-mediated signaling, have been extensively investigated as potential therapeutic strategies for brain diseases, given that p75NTR, a common neurotrophin receptor, also contributes to cell death under a variety of pathological conditions such as neurodegeneration. Since the downregulation of the BDNF/TrkB system is associated with the pathophysiology of neurodegenerative diseases and psychiatric disorders, understanding how alterations in the BDNF/TrkB system contribute to disease progression could provide valuable insight for the prevention of these brain diseases. The present review shows recent advances in the molecular mechanisms underlying the BDNF/TrkB system in neuronal survival and plasticity, providing critical insights into the potential therapeutic impact of BDNF mimetics in the pathophysiology of brain diseases. Full article

Neurotrophins are proteins that mediate neuronal development using spatiotemporal signaling gradients. The chicken nucleus magnocellularis (NM), an analogous structure to the mammalian anteroventral cochlear nucleus, provides a model system in which signaling between the brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) is temporally regulated. In the NM, TrkB expression is high early in development (embryonic [E] day 9) and is downregulated until maturity (E18–21). It is currently unknown how BDNF–TrkB signaling affects neuronal properties throughout development and across a spatial (i.e., frequency) axis. To investigate this, we exogenously applied BDNF onto NM neurons ex vivo and studied intrinsic properties using whole-cell patch clamp electrophysiology. Early in development (E13), when TrkB expression is detectable with immunohistochemistry, BDNF application slowed the firing of high-frequency NM neurons, resembling an immature phenotype. Current measurements and biophysical modeling revealed that this was mediated by a decreased conductance of the voltage-dependent potassium channels. Interestingly, this effect was seen only in high-frequency neurons and not in low-frequency neurons. BDNF–TrkB signaling induced minimal changes in late-developing NM neurons (E20–21) of high and low frequencies. Our results indicate that normal developmental downregulation of BDNF–TrkB signaling promotes neuronal maturation tonotopically in the auditory brainstem, encouraging the appropriate development of neuronal properties. Full article

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure–activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors. Full article

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced “track”). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkB^BDNF, TrkC^NT−3, TrkA^NGF, and TrkA^pro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkA^NGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkA^NGF, TrkA^pro-NGF, TrkB^BDNF, and TrkC^NT−3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients. Full article

The effect of a high-fat diet (HFD) on mood is a widely debated topic, with the underlying mechanisms being poorly understood. This study explores the anxiolytic effects of a four-week HFD in C57BL/6 mice. Five-week-old mice were exposed to either an HFD (60% calories from fat) or standard chow diet (CD) for four weeks, followed by cannula implantation, virus infusion, behavioral tests, and biochemical assays. Results revealed that four weeks of an HFD induced anxiolytic-like behaviors and increased the protein levels of mature brain-derived neurotrophic factor (mBDNF) and phosphorylated tyrosine kinase receptor B (p-TrkB) in the medial prefrontal cortex (mPFC). Administration of a BDNF-neutralizing antibody to the mPFC reversed HFD-induced anxiolytic-like behaviors. Elevated BDNF levels were observed in both neurons and astrocytes in the mPFC of HFD mice. Additionally, these mice exhibited a higher number of dendritic spines in the mPFC, as well as upregulation of postsynaptic density protein 95 (PSD95). Furthermore, mRNA levels of the N6-methyladenosine (m6A) demethylase, fat mass and obesity-associated protein (FTO), and the hydrolase matrix metalloproteinase-9 (MMP9), also increased in the mPFC. These findings suggest that an HFD may induce FTO and MMP9, which could potentially regulate BDNF processing, contributing to anxiolytic-like behaviors. This study proposes potential molecular mechanisms that may underlie HFD-induced anxiolytic behaviors. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option. Full article

Specific subpopulations of neurons in nerve and sensory systems must be developed and maintained, and this is accomplished in significant part by neurotrophins (NTs) and the signaling receptors on which they act, called tyrosine protein kinase receptors (Trks). The neurotrophins–tyrosine protein kinase receptors (NTs/Trks) system is involved in sensory organ regulation, including the visual system. An NTs/Trks system alteration is associated with neurodegeneration related to aging and diseases, including retinal pathologies. An emergent model in the field of translational medicine, for instance, in aging study, is the annual killifish belonging to the Nothobranchius genus, thanks to its short lifespan. Members of this genus, such as Nothobranchius guentheri, and humans share a similar retinal stratigraphy. Nevertheless, according to the authors’ knowledge, the occurrence and distribution of the NTs/Trks system in the retina of N. guentheri has never been investigated before. Therefore, the present study aimed to localize neurotrophin BDNF, NGF, and NT-3 and TrkA, TrkB, and TrkC receptors in the N. guentheri retina using the immunofluorescence method. The present investigation demonstrates, for the first time, the occurrence of the NTs/Trks system in N. guentheri retina and, consequently, the potential key role of these proteins in the biology and survival of the retinal cells. Full article

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT_2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT_1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs. Full article

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10–20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures. Full article

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT₄ receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT₄ receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders. Full article

Despite the increasing availability of antidepressant drugs, a high rate of patients with major depression (MDD) does not respond to pharmacological treatments. Brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling is thought to influence antidepressant efficacy and hippocampal volumes, robust predictors of treatment resistance. We therefore hypothesized the possible role of BDNF and neurotrophic receptor tyrosine kinase 2 (NTRK2)-related polymorphisms in affecting both hippocampal volumes and treatment resistance in MDD. A total of 121 MDD inpatients underwent 3T structural MRI scanning and blood sampling to obtain genotype information. General linear models and binary logistic regressions were employed to test the effect of genetic variations related to BDNF and NTRK2 on bilateral hippocampal volumes and treatment resistance, respectively. Finally, the possible mediating role of hippocampal volumes on the relationship between genetic markers and treatment response was investigated. A significant association between one NTRK2 polymorphism with hippocampal volumes and antidepressant response was found, with significant indirect effects. Our results highlight a possible mechanistic explanation of antidepressant action, possibly contributing to the understanding of MDD pathophysiology. Full article

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 $\mathsf{\beta }$ 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. Full article

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. Full article

(1) Background: The main objectives of our study are (i) to determine the prevalence of NTRK (neurotrophic tyrosine kinase) fusions in a routine diagnostic setting in NSCLC (non-small cell lung cancer) and (ii) to investigate the feasibility of screening approaches including immunohistochemistry (IHC) as a first-line test accompanied by fluorescence in situ hybridization (FISH) and RNA-(ribonucleic acid-)based next-generation sequencing (RNA-NGS). (2) Methods: A total of 1068 unselected consecutive patients with NSCLC were screened in two scenarios, either with initial IHC followed by RNA-NGS (n = 973) or direct FISH testing (n = 95). (3) Results: One hundred and thirty-three patients (14.8%) were IHC positive; consecutive RNA-NGS testing revealed two patients (0.2%) with NTRK fusions (NTRK1-EPS15 (epidermal growth factor receptor pathway substrate 15) and NTRK1-SQSTM1 (sequestosome 1)). Positive RNA-NGS was confirmed by FISH, and NTRK-positive patients benefited from targeted treatment. All patients with direct FISH testing were negative. RNA-NGS- or FISH-positive results were mutually exclusive with alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), ROS1 (ROS proto-oncogene 1), BRAF (proto-oncogene B-Raf), RET (rearranged during transfection) or KRAS (kirsten rat sarcoma viral oncogene). Excluding patients with one of these alterations raised the prevalence of NTRK-fusion positivity among panTrk-(tropomyosin receptor kinase-) IHC positive samples to 30.5%. (4) Conclusions: NTRK fusion-positive lung cancers are exceedingly rare and account for less than 1% of patients in unselected all-comer populations. Both RNA-NGS and FISH are suitable to determine clinically relevant NTRK fusions in a real-world setting. We suggest including panTrk-IHC in a diagnostic workflow followed by RNA-NGS. Excluding patients with concurrent molecular alterations to EGFR/ALK/ROS1/BRAF/RET or KRAS might narrow the target population. Full article