Search Results (423)

Cancer-related cognitive impairment (CRCI)—encompassing anxiety, depression, and memory deficits—significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer. Full article

As typical environmental hormones, endocrine-disrupting chemicals (EDCs) have become a global environmental health issue of high concern due to their property of interfering with the endocrine systems of organisms. As a commonly used substitute for bisphenol A (BPA), bisphenol E (BPE) has been frequently detected in environmental matrices such as soil and water in recent years. Existing research has unveiled the developmental and reproductive toxicity of BPE; however, only one in vitro cellular experiment has preliminarily indicated potential neurotoxic risks, with its underlying mechanisms remaining largely unelucidated in the current literature. Potential toxic mechanisms and action targets of BPE were predicted using the zebrafish model via network toxicology and molecular docking, with RT-qPCRs being simultaneously applied to uncover neurotoxic effects and associated mechanisms of BPE. A significant decrease (p < 0.05) in the frequency of embryonic spontaneous movements was observed in zebrafish at exposure concentrations ≥ 0.01 mg/L. At 72 hpf and 144 hpf, the larval body length began to shorten significantly from 0.1 mg/L to 1 mg/L, respectively (p < 0.01), accompanied by a reduced neuronal fluorescence intensity and a shortened neural axon length (p < 0.01). By 144 hpf, the motor behavior in zebrafish larvae was inhibited. Through network toxicology and molecular docking, HSP90AB1 was identified as the core target, with the cGMP/PKG signaling pathway determined to be the primary route through which BPE induces neurotoxicity in zebrafish larvae. BPE induces neuronal apoptosis and disrupts neurodevelopment by inhibiting the cGMP/PKG signaling pathway, ultimately suppressing the larval motor behavior. To further validate the experimental outcomes, we measured the expression levels of genes associated with neurodevelopment (elavl3, mbp, gap43, syn2a), serotonergic synaptic signaling (5-ht1ar, 5-ht2ar), the cGMP/PKG pathway (nos3), and apoptosis (caspase-3, caspase-9). These results offer crucial theoretical underpinnings for evaluating the ecological risks of BPE and developing environmental management plans, as well as crucial evidence for a thorough comprehension of the toxic effects and mechanisms of BPE on neurodevelopment in zebrafish larvae. Full article

Despite growing evidence supporting the efficacy of LSD-assisted psychotherapy in treating major depressive disorder (MDD), identifying reliable psychopharmacological biomarkers remains necessary. Oxytocin, a neuropeptide implicated in social bonding and flexibility, is a promising candidate due to its release following serotonergic psychedelic administration in healthy individuals; however, its dynamics in psychiatric populations are currently unexplored. This observational pilot study aimed to characterize salivary oxytocin dynamics during a single LSD-assisted psychotherapy session in our patients with treatment-resistant MDD. Participants received 100 or 150 µg LSD, and salivary oxytocin was measured at baseline, 60, 90, and 180 min post-LSD. Concurrently, participants rated subjective drug intensity (0–10 scale) at 60, 90, and 180 min. A linear mixed model revealed significant variation of oxytocin levels over time. Perceived psychedelic intensity also significantly varied over time. This supports oxytocin as a potential biomarker. Larger, controlled trials are warranted to replicate these findings and clarify the mechanistic links between oxytocin dynamics and clinical outcomes, including changes in depressive symptoms and mental flexibility. Full article

Sedation and anesthesia are essential for ensuring animal welfare during surgical procedures such as hernia repair in swine. However, the number of sedative and anesthetic agents officially approved for livestock use remained limited. This study evaluated the sedative efficacy and serotonergic effects of a romifidine/ketamine/diazepam protocol, with and without the addition of tramadol, in swine undergoing umbilical hernia repair. Sixty-six crossbred Large White swine were randomly allocated to three groups: LL (lidocaine 4 mg/kg by infiltration), LT (lidocaine 2 mg/kg by infiltration + tramadol 2 mg/kg intraperitoneally), and TT (lidocaine2 mg/kg by infiltration + tramadol 4 mg/kg intraperitoneally). The physiological parameters heart rate, arterial pressure, oxygen saturation, rectal body temperature, and respiratory rate were assessed. The depth of intraoperative anesthesia and postoperative sedation was assessed using an ordinal scoring system (0–3). Plasma serotonin (5-HT) concentration was measured at baseline and 24 h post-surgery. Physiological parameters remained within species-specific reference ranges throughout the procedure. Anesthesia depth scores significantly decreased over time in all groups (p ≤ 0.001), with the tramadol-treated groups (LT and TT) showing more prolonged deeper anesthesia. Postoperative sedation was significantly higher in the TT group (p ≤ 0.001). Serotonin concentration decreased in LL, increased in LT, and remained stable in TT. These findings suggest that tramadol may enhance sedation and recovery, potentially through serotonergic modulation. Moreover, serotonin could serve as a physiological marker warranting further investigation in future studies of anesthetic protocols in veterinary medicine. Full article

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of mortality among individuals with epilepsy, particularly those with drug-resistant forms. This review explores the complex multisystem mechanisms underpinning SUDEP, integrating recent findings on brain, cardiac, and pulmonary dysfunctions. Background/Objectives: The main objective of this review is to elucidate how seizures disrupt critical physiological systems, especially the brainstem, heart, and lungs, contributing to SUDEP, with emphasis on respiratory control failure and autonomic instability. Methods: The literature from experimental models, clinical observations, neuroimaging studies, and genetic analyses was systematically examined. Results: SUDEP is frequently preceded by generalized tonic–clonic seizures, which trigger central and obstructive apnea, hypoventilation, and cardiac arrhythmias. Brainstem dysfunction, particularly in areas such as the pre-Bötzinger complex and nucleus tractus solitarius, plays a central role. Genetic mutations affecting ion channels (e.g., SCN1A, KCNQ1) and neurotransmitter imbalances (notably serotonin and GABA) exacerbate autonomic dysregulation. Risk is compounded by a prone sleeping position, reduced arousal capacity, and impaired ventilatory responses. Conclusions: SUDEP arises from a cascade of interrelated failures in respiratory and cardiac regulation initiated by seizure activity. The recognition of modifiable risk factors, implementation of monitoring technologies, and targeted therapies such as serotonergic agents may reduce mortality. Multidisciplinary approaches integrating neurology, cardiology, and respiratory medicine are essential for effective prevention strategies. 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

Sleep paralysis (SP), an REM parasomnia, can be characterized as one of the symptoms of narcolepsy. The SP phenomenon involves regaining meta-consciousness by the dreamer during REM, when the physiological atonia of skeletal muscles is accompanied by visual and auditory hallucinations that are perceived as vivid and distressing nightmares. Sensory impressions include personification of an unknown presence, strong chest pressure sensation, and intense fear resulting from subjective interaction with the unfolding nightmare. While the mechanism underlying skeletal muscle atonia is known, the physiology of hallucinations remains unclear. Their complex etiology involves interactions among various membrane receptor systems and neurotransmitters, which leads to altered neuronal functionality and disruptions in sensory perception. According to current knowledge, serotonergic activation of 5-hydroxytryptamine-receptor-2A (5-HT2A)-associated pathways plays a critical role in promoting hallucinogenesis during SP. Furthermore, they share similarities with psychedelic-substance-induced ones (i.e., LSD, psilocybin, and 2,5-dimethoxy-4-iodoamphetamine). These compounds also target the 5-HT2A receptor; however, their molecular mechanism varies from serotonin-induced ones. The current review discusses the intracellular signaling pathways responsible for promoting hallucinations in SP, highlighting the critical role of β-arrestin-2. We propose that the β-arrestin-2 signaling pathway does not directly induce hallucinations but creates a state of network susceptibility that facilitates their abrupt emergence in sensory areas. Understanding the molecular basis of serotonergic hallucinations and gaining better insight into 5-HT2A-receptor-dependent pathways may prove crucial in the treatment of multifactorial neuropsychiatric disorders associated with the dysfunctional activity of serotonin receptors. Full article

Hypoxia can adversely affect multiple organ systems. This study investigated the impact of intermittent hypoxia on serotonin levels and depression-like behaviors across distinct neuroanatomical regions. Sixteen adult female Wistar albino rats were divided into two groups: control (n = 8) and hypoxia (n = 8). The hypoxia group was exposed to a simulated altitude of 3000 for 5 h daily over 14 days. Behavioral assessments included locomotor activity (open field test) and depression-like behaviors (forced swimming test). Serotonin levels were quantified via ELISA in the prefrontal cortex, striatum, thalamus, hypothalamus, hippocampus, and serum. Intermittent hypoxia did not alter locomotor activity (p > 0.05) but significantly increased depression-like behavior (p < 0.05), accompanied by a pronounced reduction in swimming behavior (p < 0.0001), a marker associated with serotonergic function. Serotonin levels were significantly reduced in the prefrontal cortex (p < 0.005) and striatum (p < 0.05), while no changes were observed in other regions or serum (p > 0.05). These findings demonstrate that intermittent hypoxia induces depression-like behaviors and region-specific serotonin depletion, particularly in the prefrontal cortex and striatum. This underscores the need to evaluate hypoxia-related brain health implications in conditions such as sleep apnea and acute mountain sickness. Full article

The hypothalamus belongs to the central brain structure designed for the neuroendocrine regulation of many organismal functions, including the stress response, cardiovascular system, and blood pressure, and it is well known that the serotonergic hypothalamic system plays a significant role in these processes. Unfortunately, the genetic determination of serotonergic hypothalamic mechanisms has been little studied. The aim of this article is to describe the expression profile of the genes in the hypothalamic serotonergic synapses in hypertensive ISIAH rats in comparison with normotensive WAG rats in control conditions and under the influence of a single short-term restraint stress. It was found that 14 differentially expressed genes (DEGs) may provide the inter-strain differences in the serotonergic synaptic function in the hypothalamus between the hyper- and normotensive rats studied. In hypertensive rats, downregulation of Slc18a1 gene in the presynaptic serotoninergic ends and decreased expression of Cacna1s and Htr3a genes determining the postsynaptic membrane conductance may be considered as a main factors causing differences in the function of hypothalamic serotoninergic synapses in hypertensive ISIAH and normotensive WAG rats at the basal conditions. Under basal conditions, glial cell genes were not involved in the formation of inter-strain differences in serotonergic synaptic function. The analysis of transcriptional responses to restraint stress revealed key genes whose expression is involved in the regulation of serotonergic signaling, and a cascade of interrelated changes in biological processes and metabolic pathways. Stress-dependent changes in the expression of some DEGs are similar in the hypothalamus of hypertensive and normotensive rats, but the expression of a number of genes changes in a strain-specific manner. The results suggest that in hypothalamic glial cells of both strains, restraint stress induces changes in the expression of DEGs associated with the synthesis of Ip3 and its receptors. Many of the identified serotonergic DEGs participate in the regulation of not only serotonergic synapses but may also be involved in the regulation of cholinergic, GABAergic, glutamatergic, and dopaminergic synapses. The results of the study provide new information on the genetic mechanisms of inter-strain differences in the functioning of the hypothalamic serotonergic system in hypertensive ISIAH and normotensive WAG rats at rest and under the influence of a single short-term restraint (emotional) stress. Full article

Cholinergic neuron impairment is a significant cause of cognitive decline in Alzheimer’s disease (AD), making acetylcholinesterase (AChE) a key therapeutic target. AChE inhibitors are principal drugs prescribed to alleviate symptoms in AD patients, while up to 50% of these individuals also suffer from depression, frequently treated with selective serotonin reuptake inhibitors (SSRIs). Due to the multisymptomatic nature of AD, there is a growing interest in developing multitargeted ligands that simultaneously enhance cholinergic and serotonergic tone. This study presents the synthesis of novel ligands based on functionalized piperidines, evaluated through radioligand binding assays at the serotonin transporter (SERT) and AChE and butyrylcholinesterase (BuChE) inhibition. The pharmacological results showed that some compounds exhibited moderate inhibitory activity against AChE, with one compound 19 standing out as the most potent, also displaying a moderate BuChE inhibitory activity, while showing low affinity for SERT. On the other hand, compound 21 displayed an interesting polypharmacological profile, with good and selective activity against BuChE and SERT. The results underscore the difficulty of designing promiscuous ligands for these targets and suggest that future structural modifications could optimize their therapeutic potential in AD. Full article

Sceletium tortuosum (ST) induces antidepressant and anxiolytic effects, purportedly by monoamine regulation, anti-inflammatory and antioxidant properties, and phosphodiesterase 4 (PDE4) inhibition. These multimodal actions have not been demonstrated in an animal model of major depressive disorder. Wistar rats (both sexes) were subjected to 8-week unpredictable chronic mild stress, subsequently receiving saline, a standardized ST extract, Zembrin^® 25 and 12.5 mg/kg (ZEM25 and ZEM12.5), its primary alkaloid mesembrine (MES), or escitalopram (20 mg/kg) for 36 days. Sucrose preference, open field, Barnes maze, and forced swim tests were performed, with cortico-hippocampal monoamines, inflammatory and oxidative stress markers analyzed post-mortem. Male, but not female rats, presented with increased anhedonia and anxiety but not despair. Males presented with increased hippocampal PDE4B expression, increased dopamine metabolites, and decreased cortical serotonin. In males, ZEM12.5 decreased anhedonia- and anxiety-like behavior, decreased cortical and hippocampal PDE4B, and increased plasma interleukin-10. MES induced a transient decrease in anhedonia-like behavior and increased hippocampal serotonergic and cortical dopaminergic activity, whilst decreasing hippocampal PDE4B. ZEM25 increased plasma interleukin-10 but decreased cortical glutathione, indicating paradoxical anti-inflammatory and prooxidant effects. ZEM12.5 and MES more effectively addressed anxious–depressive-like behavior and stress-induced inflammation and monoaminergic alterations, respectively. Multitargeted actions on monoamines, redox-inflammation, and PDE4 may provide ST with antidepressant effects across multiple symptom domains, although mutually synergistic/antagonistic effects of constituent alkaloids should be considered. Full article

Endogenous opioids, such as Endomorphin-2, are not typically associated with severe constipation, unlike pharmaceutical opioids, which induce opioid-induced constipation (OIC) by activating μ-opioid receptors in the gastrointestinal tract. In this study, we present a mathematical model, which integrates the serotonergic and opioid pathways, simulating the interaction between serotonin and opioid signaling within the enteric nervous system (ENS). The model explores the mechanisms underlying OIC, with a focus on the change in adenylyl cyclase (AC) activity, cAMP accumulation, and the distinct functionalities of Endomorphin-2 compared to commonly used pharmaceutical opioids. We study the effects of Morphine, Fentanyl, and Methadone and contrast them with Endomorphin-2. Our findings reveal that opioids do not perturb the signaling of serotonin, but only the activity of AC, suggesting that serotonin levels have no influence on improving opioid-induced constipation. Furthermore, this study reveals that the primary difference between endogenous and pharmaceutical opioids is their degradation rates. This finding shows that modulating opioid degradation rates significantly improves cAMP recovery. In conclusion, our insights steer towards exploring opioid degrading enzymes, localized to the gut, as a strategy for mitigating OIC. Full article

The area postrema (AP) is a circumventricular organ (CVO) at the base of the fourth ventricle. It has a crucial role in regulating nausea and vomiting due to its unique blood–brain barrier (BBB)-permeability and extensive neural connectivity. Here, we present two cases of area postrema syndrome (APS), a rare condition of intractable nausea and vomiting resulting from direct AP injury. Our cases each occurred in the context of infratentorial neoplasms or their treatment. Using these cases as a framework, we review the literature on central emetic pathways and propose a treatment algorithm for managing refractory nausea and vomiting of central origin. We also highlight other targets beyond conventional serotonergic, dopaminergic, or histaminergic blockade and their roles in central hyperemesis. Our literature review suggests that APS is due to the disruption of the baseline inhibitory tone of outgoing AP signals. When other options fail, our algorithm culminates in the off-label use of combined serotonergic and neurokinin-1 blockade, which is otherwise used to manage chemotherapy-induced nausea and vomiting (CINV). We believe multimodal CNS receptor blockade is efficacious in APS because it addresses the underlying central neural dysregulation, rather than solely targeting peripheral emetic triggers. Full article

The 2018 Farm Bill legalized hemp-derived cannabidiol (CBD) products containing less than 0.3% tetrahydrocannabinol (THC) in the United States. This legislative shift catalyzed both public and scientific interest in CBD’s potential health benefits. However, the rapid expansion of the CBD market has considerably outpaced rigorous scientific research, leaving many health claims largely unsubstantiated. While preclinical studies suggest that CBD may exert antitumorigenic effects in colorectal cancer (CRC) by modulating cell proliferation, apoptosis, and inflammation, clinical evidence supporting these effects remains limited. This review critically examines the current evidence on the role of CBD in colorectal tumorigenesis, with particular attention to its molecular mechanisms and interactions with the serotonergic system—a signaling pathway implicated in the development of CRC and possessing potential dual anti- and pro-tumorigenic properties. By influencing the serotonergic system, CBD may confer both protective and potentially deleterious effects during CRC development. This review underscores the need for further research to elucidate the complex mechanisms of CBD in colorectal tumorigenesis and to evaluate its therapeutic potential in clinical settings. Understanding these interactions could pave the way for novel prevention and treatment strategies, optimizing the anticancer efficacy of CBD while mitigating unintended risks. Full article

In West Africa, Paullinia pinnata (P. pinnata) alcohol leaf extracts are used to treat disorders such as depression and anxiety with no documented scientific justification. We have therefore evaluated the potential anxiolytic and antidepressant effects of Paullinia pinnata methanol leaf extract (PPME) in mice, along with probable underlying mechanisms. Adult Swiss albino mice were administered 100, 200, and 400 mg/kg of PPME orally before subjecting them through elevated plus maze (EPM) and hole-board tests to assess the anxiolytic effect. The tail suspension test (TST) and the forced swim test (FST) were used to assess the antidepressant-like effects. Reserpine, labetalol, and risperidone were used to investigate probable mechanisms of action. In both FST and TST, the duration of immobility was considerably reduced by PPME. Conversely, PPME had no significant effect on the number of mice who dipped their heads into the hole-board or entered the EPM’s open arm. Mechanistic analysis revealed that in mice given labetalol or risperidone beforehand, PPME dramatically reduced the length of immobility and reversed ptosis and akinesia caused by reserpine. Our findings suggest that PPME possesses antidepressant-like, but not anxiolytic-like, effects in mice, and antidepressant action may involve enhancing noradrenergic and serotonergic mechanisms. Full article