Search Results (156)

Background: Neuroblastoma is the most common extracranial solid malignancy in infants and children. High-risk neuroblastoma patients are commonly treated with temozolomide (TMZ), which typically exhibits a poor therapeutic response. Serotonin, also known as 5-hydroxytryptamine (5-HT), plays various essential functions in the human body. In the central nervous system, it serves as a neurotransmitter. Beyond its physiological roles, 5-HT has recently been identified as a potential growth factor for several human tumors, including gliomas and carcinoid tumors. Recent literature has demonstrated that 5-HT receptor antagonists can inhibit the growth of cancer cells. Furthermore, both 5-HT receptors and their antagonists have been identified as potential anticancer agents, suggesting their significance in the development of new treatment strategies. Objectives: The primary aim of this study was to examine the effects of 5-HT and 5-HT antagonists on tumor (neuroblastoma (SH-SY5Y)) and healthy cells (microglia (HMC3)) and determine the impact of their interaction with the anticancer agent TMZ on cell proliferation/viability and migration. Methods: The study explored the interaction between 5-HT, the 5-HT antagonist granisetron (GRN), the anticancer agent TMZ, and their combinations, specifically assessing their influence on cell proliferation, viability, and migration. Results: As a result, the single and combined applications of 5-HT, TMZ, and GRN, a 5-HT antagonist, inhibited cell growth and proliferation in SH-SY5Y, causing decreased cell viability. Additionally, the combination of 5-HT and GRN increased the efficacy of TMZ. Conclusions: The study findings revealed that 5-HT and 5-HT antagonists may have therapeutic effects by exhibiting antiproliferative effects in SH-SY5Y cells at high concentrations. Full article

Background: Burning Mouth Syndrome (BMS) is a nociplastic pain condition characterized by altered central nervous system pain processing, significantly impacting patient quality of life. Pharmacological management often involves amitriptyline (monotherapy) and aripiprazole (for refractory cases) in Japan. However, the therapeutic efficacy of these drugs in BMS frequently exhibits a non-sigmoid (U-shaped or bell-shaped) dose–response relationship, indicating a clinically effective dose that is often considerably lower than those used for their primary indications and challenging conventional pharmacological assumptions. Method: This paper synthesizes existing pharmacological knowledge to elucidate the mechanisms underlying the non-dose-dependent actions of amitriptyline and aripiprazole in BMS. It focuses on their specific interactions with key neurotransmitter systems and receptors, particularly N-methyl-D-aspartate (NMDA) receptors and dopamine D2 receptors, to explain the observed non-linear dose–response and the importance of identifying a personalized therapeutic window. Result: Amitriptyline demonstrates efficacy in BMS at low doses (e.g., 25 mg), primarily through its action as an NMDA receptor antagonist via calcium-dependent desensitization and open-channel block, addressing central sensitization. Its effects are distinct from its antidepressant actions, and the “serotonin paradox” highlights the complexity of serotonin’s role in pain. Aripiprazole, utilized for refractory BMS, acts as a dopamine D2 receptor partial agonist, leading to a non-linear dose–response where sustained therapeutic effect is observed at specific low doses (e.g., 1.7–1.8 mg/day). This non-linearity is attributed to partial agonism, alongside interactions with serotonin 5-HT1A and 5-HT2A receptors. The general non-dose-dependency for both drugs is further explained by phenomena such as multiple binding sites with differing affinities, receptor desensitization/downregulation, activation of counter-regulatory mechanisms, and hormesis. Discussion: The observed non-linear dose–response curves for amitriptyline and aripiprazole in BMS underscore the inadequacy of a “one-size-fits-all” treatment approach. This necessitates a shift towards personalized medicine, which considers individual patient factors including pharmacogenomics, comorbidities, age, organ function, and psychological/social profiles. The true “personalized therapeutic window” is a balance between achieving significant pain relief and minimizing adverse effects, emphasizing careful titration and patient-centered care. Conclusions: The pharmacological actions of amitriptyline and aripiprazole in BMS are not linearly dose-dependent, but rather exhibit a personalized therapeutic window driven by complex interactions with NMDA and D2 receptors and adaptive physiological responses. This intricate pharmacological landscape mandates a personalized medicine approach to optimize treatment outcomes, improve patient adherence, and enhance the quality of life for individuals suffering from this challenging nociplastic pain condition. Full article

Serotonin or 5-hydroxytryptamine (5-HT) has been implicated in promoting cancer cell growth by acting on 5-HT receptors, such as 5-HT1 and 5-HT2 receptors. However, the role of 5-HT3 receptor antagonists in gastric cancer cell lines remains unclear. This study aimed to evaluate the effect of 5-HT3 receptor antagonists (ondansetron, palonosetron, and ramosetron) on cancer cell growth using AGS and MKN-1 cell lines, as well as the xenograft mouse model. All the three antagonists inhibited cell proliferation, migration, and colony formation in AGS cells. Specifically, palonosetron induced G1 cell cycle arrest, autophagy, and phosphorylation of GSK3β, along with increased expression of p27, p53, and LC3B. In vivo studies demonstrated that palonosetron reduced tumor growth and modulated pro-inflammatory cytokines—tumor necrosis factor alpha, interleukin 6, and interleukin 1β. These findings suggest that 5-HT3 receptor antagonists, especially palonosetron, exert anti-tumor effects in gastric cancer through G1 cell cycle regulation and immunomodulation. The results position palonosetron as a promising lead for further preclinical development in gastric cancer. Full article

Extensive research has focused on developing anti-nociceptive therapy by targeting specific molecular pathways. Among these, the serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators of neuropathic pain. However, the therapeutic potential of their simultaneous inhibition remains largely unexplored. In this study, we evaluated the efficacy of dual antagonism of 5-HT2AR and mGluR5 using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague–Dawley rats. Co-administration of selective antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, as evidenced by increased withdrawal thresholds and reduced pain-related behaviors compared to monotherapy. The analgesic efficacy of dual antagonism was comparable to that of gabapentin and morphine. Additionally, novel small molecules designed to concurrently inhibit 5-HT2AR and mGluR5 exerted dose-dependent anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Importantly, unlike morphine, repeated administration of the dual antagonist maintained anti-allodynic efficacy with a low potential of abuse. These findings may indicate the promise of simultaneous 5-HT2AR and mGluR5 antagonism as a novel and potentially safer strategy for managing chronic neuropathic pain. Full article

Background: Patients with sepsis-associated encephalopathy (SAE) present with cognitive impairments. Serotonergic neurotransmission plays a critical role in regulating cognitive processes, and its dysfunction may contribute to SAE-related deficits. However, the effect of 5-hydroxytryptophan (5-HTP), a direct serotonin precursor, on SAE has not been investigated. We hypothesized that 5-HTP could alleviate cognitive dysfunction in SAE. Methods: The SAE mouse model was induced via intraperitoneal administration of lipopolysaccharide (LPS, 10 mg/kg). Cognitive function and locomotor activity were assessed using the Barnes maze, novel object recognition test, and open-field test to evaluate the effects of 5-hydroxytryptophan (5-HTP). Additionally, WAY100635, a selective 5-HT1A receptor antagonist, was co-administered with 5-HTP to investigate the potential mechanisms underlying its effects on SAE-related cognitive dysfunction. The effects of 5-HTP and WAY100635 on cognition and motor activity were also investigated in healthy mice. Results: LPS-induced sepsis caused a learning deficit. A dose of 10 mg/kg 5-HTP improved cognitive dysfunction, whereas doses of 25 and 100 mg/kg worsened cognitive dysfunction. Moreover, 100 mg/kg 5-HTP increased mortality in SAE mouse models. Neither 5-HTP (10 mg/kg) nor WAY100635 (1 mg/kg) alone exerted a significant impact on the locomotor activity or cognitive function of healthy mice. The cognition-enhancing effect of 5-HTP (10 mg/kg) was reversed by WAY100635 (1 mg/kg). Conclusions: improvement in cognitive dysfunction by 5-HTP suggests that serotonergic transmission plays a role in the pathophysiology of SAE, and 5-HTP, an over-the-counter supplement approved for human use, may hold clinical potential for the prevention and treatment of SAE. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Neuropathic pain resulting from injury to the somatosensory nervous system affects approximately 6.9–10% of the general population and significantly impacts quality of life. Common presentations include burning, stabbing, tingling, or electrical sensations, occurring spontaneously or through hyperalgesia or allodynia. Treatment approaches follow a tiered system. First-line therapies include gabapentinoids (e.g., gabapentin, pregabalin), which target voltage-gated calcium channels; tricyclic antidepressants (e.g., amitriptyline, nortriptyline); and serotonin-norepinephrine reuptake inhibitors such as duloxetine. Second-line options encompass topical agents (e.g., 5% lidocaine, 8% capsaicin), opioid-like medications (e.g., tramadol, tapentadol), and adjunctive therapies including psychological therapies and lifestyle interventions. For refractory cases, third-line treatments include NMDA receptor antagonists (e.g., ketamine, dextromethorphan), cannabinoids, and botulinum toxin type A, though these have more limited clinical evidence. Procedural interventions such as spinal cord stimulation and transcutaneous electrical nerve stimulation provide alternatives when pharmacological approaches fail. Despite advances in treatment options, many patients remain undertreated, highlighting the need for individualized, multimodal approaches and continued research into the complex pathophysiology of neuropathic pain conditions. Full article

Coronary artery disease (CAD) and peripheral artery disease (PAD) are associated with increased blood viscosity, which contributes to vascular inflammation and impaired microcirculation. Blood viscosity plays a crucial role in disease progression, influencing endothelial function and tissue perfusion. Sarpogrelate hydrochloride, a serotonin receptor antagonist, has antiplatelet and vasodilatory properties that may improve microvascular function and blood rheology. This randomized, parallel-group, open-label, single-center, phase IV clinical trial enrolled 68 patients with both CAD and PAD. The participants were randomized in a 1:1 ratio to receive either aspirin monotherapy (100 mg) or aspirin (100 mg) plus sarpogrelate (300 mg) for 12 weeks. The primary outcome was the change in blood viscosity from baseline to week 12, assessed using the scanning capillary technique. Secondary outcomes included erythrocyte deformability, flow-mediated dilation (FMD), and tissue oxygen delivery index (tODI), which collectively provide insights into microvascular function and oxygen transport efficiency. Elevated blood viscosity is a key factor in cardiovascular disease progression, yet conventional antiplatelet therapy has shown limited effects on hemorheology. Sarpogrelate, by targeting serotonin-mediated pathways, may enhance microcirculatory function and optimize vascular health. These effects could lead to better oxygen delivery and overall vascular health, thereby optimizing cardiovascular outcomes. By integrating hemorheological and vascular markers, this study aims to provide evidence on the potential benefits of combination therapy. Findings could inform optimized antiplatelet strategies to improve vascular health and reduce cardiovascular risk in patients with CAD and PAD. Full article

Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. However, off-target interactions were not assessed, which may influence their overall safety profile. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions and enhanced pharmacokinetics, suggesting potential neuropsychiatric applications. However, their safety and efficacy remain to be validated through in vitro and in vivo studies. Until such validation is performed, these derivatives should be considered as promising candidates with optimized receptor binding rather than confirmed safer alternatives. Full article

Background and Objectives: Serotonin modulates platelet aggregation and secretion, but its role in hemostasis remains controversial. This study hypothesized that the 5-HT₃ receptor antagonist palonosetron may inhibit platelet function and aimed to evaluate its effects on blood coagulation using thromboelastography (TEG). Materials and Methods: Blood samples from 11 healthy volunteers were treated with palonosetron at concentrations of 25, 250, and 2500 ng/mL. Untreated samples served as controls. Coagulation parameters were assessed using global hemostasis (citrated kaolin, citrated rapid TEG, citrated kaolin with heparinase, and citrated functional fibrinogen) and PlateletMapping (adenosine diphosphate [ADP], arachidonic acid, and others) assays. Results: In the global hemostasis assay, maximum amplitude values, reflecting clot strength, decreased with increasing palonosetron concentrations in all tests, including citrated kaolin (p = 0.031), citrated rapid TEG (p = 0.001), citrated kaolin with heparinase (p = 0.033), and citrated functional fibrinogen (p = 0.011). The PlateletMapping assay showed significant reductions in ADP-induced platelet aggregation (p = 0.001), with the largest inhibition observed at 2500 ng/mL (p = 0.007). Despite these changes, all values remained within normal reference ranges. Conclusions: Palonosetron induces hypocoagulable trends in vitro by inhibiting platelet function and fibrinogen-mediated clot strength. However, these changes are unlikely to result in clinically significant hemostatic impairment when used within therapeutic doses. Further research is warranted to confirm these findings and explore their clinical relevance. Full article

Objective: To narratively review currently available antidepressants and future potential antidepressants as monotherapy for the treatment of depressive disorders. Methods: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), dopamine reuptake inhibitor (bupropion), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were reviewed according to the results from Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study and systematic reviews. For the rest of the antidepressants, a PubMed/Medline search was conducted with priority for systematic reviews. For drugs in development for depressive disorders, PubMed, Google, and Clinicaltrials.gov databases were used. Results: The STAR*D Study demonstrated that sertraline, venlafaxine, and bupropion monotherapy had similar efficacy in patients with major depressive disorder (MDD) who failed citalopram. A network meta-analyses of randomized, placebo-controlled trials found that SSRIs, SNRIs, bupropion, TCAs, mirtazapine, and agomelatine had similar relative efficacy compared to placebo, but had different acceptability. Gepirone had more failed/negative studies and smaller effect size relative to placebo compared to other antidepressants. The combination of dextromethorphan and bupropion, ketamine infusion, and intranasal esketamine had faster onset of action but similar effect size compared to monoamine-based antidepressants as monotherapy. Brexanolone and zuranolone are effective in postpartum depression (PPD), but the effect size of zuranolone in MDD as monotherapy or adjunctive therapy was very small. Psychedelics, glutamate receptor-related agents, kappa opioid receptor antagonists, orexin receptor antagonists, new anti-inflammatory agents, and biomarker-based antidepressant therapy have been under investigation for depressive disorders. Psychedelics showed faster onset of action, large effect size, and long durability. Conclusions: Monoamine-based antidepressants likely continue to be the mainstream antidepressants for depressive disorder. NMDA receptor antagonists and neurosteroid antidepressants will play a bigger role with the improvement of accessibility. Psychedelics may become a game changer if phase III studies validate their efficacy and safety in depressive disorders. Full article

Background/Objectives: Rodents provide a useful translational model of fear- and anxiety-related behaviors. Previously stressed animals exhibit physiological and behavioral stress responses that parallel those observed in anxious humans. Patients diagnosed with post-traumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms that result from exposure to one or more traumatic events, with individuals exposed to early adverse experiences and women having increased vulnerability for diagnoses; however, the mechanisms of this increased vulnerability remain unknown. PTSD involves a complex network of highly interconnected brain regions, including the bed nucleus of the stria terminalis (BNST). Serotonin (5-HT) release into the BNST yields an increased expression of both fear and anxiety, specifically through 5-HT_2C receptor signaling. The present experiment addressed whether 5-HT_2C receptor signaling in the BNST is necessary for the acquisition of early-life stress (ELS)-induced enhancements in adult contextual fear learning. Methods: Rats received 0 or 15 footshocks on postnatal day 17, an established model of acute ELS (aELS) that yields enhanced adult fear learning. In adulthood, rats received bilateral infusions of a vehicle, a 5-HT_2C receptor antagonist (RS-102221), or a 5-HT_2C receptor agonist (MK-212) into the BNST 15 min prior to one-footshock contextual fear conditioning in a novel context. The next day, rats were returned to the fear-conditioning context to assess their fear memory (freezing). Results: Females demonstrated aELS-induced enhancement in contextual fear learning, while males did not. BNST infusions of RS-102221 reduced contextual fear conditioning, independent of aELS condition and sex. Infusions of MK-212 had no effect. Conclusions: Taken together, these data suggest that serotonergic signaling through 5-HT_2C receptors in the BNST contributes to contextual fear conditioning, but not aELS-induced stress-enhanced fear learning (SEFL). Full article

Recent breakthroughs in the determination of atomic resolution 3-D cryo-electron microscopy structures of membrane proteins present an unprecedented opportunity for drug discovery. Structure-based drug discovery utilizing in silico methods enables the study of dynamic connectivity of stable conformations induced by the drug in achieving its effect. With the ever-expanding computational power, simulations of this type reveal protein dynamics in the nano-, micro-, and even millisecond time scales. In the present study, aiming to characterize the protein dynamics of the 5HT_2A receptor stimulated by ligands (agonist/antagonist), we performed 1 µs MD simulations on 5HT_2A/DOI (agonist), 5HT_2A/GSK215083 (antagonist), and 5HT_2A (APO, no ligand) systems. The crystal structure of 5HT_2A/zotepine (antagonist) (PDB: 6A94) was used to set up the simulation systems in a lipid bilayer environment. We found the monitoring of the ionic lock residue pair (R3.50-E6.30) of 5HT_2A in MD simulations to be a good approximation of the effects of agonists (ionic lock breakage) or antagonists (ionic lock formation) on receptor activation. We further performed analyses of the MD trajectories, including Principal Component Analysis (PCA), hydrogen bond, salt bridge, and hydrophobic interaction network analyses, and correlation between residues to identify key elements of receptor activation. Our results suggest that in order to trigger receptor activation, DOI must interact with 5HT_2A through residues V5.39, G5.42, S5.43, and S5.46 on TM5, inducing significant conformational changes in the backbone angles of G5.42 and S5.43. DOI also interacted with residues W6.48 (toggle switch) and F6.51 on TM6, causing major conformational shifts in the backbone angles of F6.44 and V6.45. These structural changes were transmitted to the intracellular ends of TM5, TM6, and ICL3, resulting in the breaking of the ionic lock and subsequent G protein activation. The studies could be helpful in future design of selective agonists/antagonists for various serotonin receptors (5HT_1A, 5HT_2A, 5HT_2B, 5HT_2C, and 5HT₇) involved in detrimental disorders, such as addiction and schizophrenia. Full article

Tegaserod (1-{[(5-methoxy-1H-indol-3-yl)methyliden]amino}-3-pentylguanidine) is a potent agonist at human recombinant 5-HT₄ serotonin receptors. Consequently, tegaserod is utilized in the treatment of bowel diseases. The objective of this study was to test the hypothesis that tegaserod stimulates human cardiac atrial 5-HT₄-receptors via cyclic adenosine monophosphate (cAMP)-dependent pathways. Tegaserod exerted positive inotropic effects (PIEs) and positive chronotropic effects (PCEs) in isolated left and right atrial preparations, respectively, from mice with cardiac-specific overexpression of the human 5-HT₄ serotonin receptor (5-HT₄-TG) in a concentration- and time-dependent manner. However, no effect was observed in the hearts of littermates of wild-type mice (WT). Western blot analysis revealed that the expression of 5-HT₄ receptors was significantly higher in 5-HT₄-TG mice compared to WT mice. The specificity of the signal for the 5-HT₄ receptor was confirmed by the absence of the signal in the hearts of 5-HT₄ receptor knockout mice. Furthermore, tegaserod increased the force of contraction (at concentrations as low as 10 nM), reduced the time of tension relaxation, and increased the rate of tension development in isolated electrically stimulated (at a rate of 60 beats per minute) human right atrial preparations (HAPs, obtained during open-heart surgery) when administered alone. The potency and efficacy of tegaserod to raise the force of contraction were enhanced in the presence of cilostamide, a phosphodiesterase III inhibitor. The positive inotropic effect of tegaserod in HAPs was found to be attenuated by the 5-HT₄ serotonin receptor antagonist GR 125487 (0.1 µM). The efficacy of tegaserod (10 µM) in raising the force of contraction in HAPs was less pronounced than that of serotonin (10 µM) or isoprenaline (1 µM). Tegaserod shifted the concentration–response curve of the force of contraction to serotonin to the right in HAPs, indicating that it is a partial agonist at 5-HT₄ serotonin receptors in this model. We propose that the mechanism of action of tegaserod in HAPs involves cAMP-dependent phosphorylation of cardiac regulatory proteins. Full article

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study’s findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease. Full article