Search Results (188)

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

Objective: Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) has been associated with altered neonatal adaptation, but its relationship with early elimination patterns remains unclear. Given the role of serotonin in gastrointestinal and urinary physiology, we aimed to evaluate the association between maternal SSRI use during pregnancy and time to first stool and time to first void in healthy neonates. Methods: In this retrospective matched cohort study, neonates exposed to SSRIs in utero were matched 1:1 with unexposed controls by gestational age (GA) and weight-for-gestational-age category. The primary outcomes were time to first void and time to first stool. Multivariable linear regression was performed using log10-transformed time to first stool, adjusting for maternal age, GA, and neonatal sex. Sensitivity analyses included size-for-gestational-age and time to first feeding. Results: A total of 266 neonates were included (133 SSRI-exposed, 133 unexposed). Time to first stool was shorter in SSRI-exposed neonates compared with unexposed neonates (median 7.4 vs. 8.6 h, p = 0.023), while the time to first void did not differ. In adjusted analysis, SSRI exposure remained associated with shorter time to first stool (β = −0.08, 95% CI −0.16 to −0.001, p = 0.035), corresponding to an approximate 17% reduction. The association was consistent across sensitivity analyses. Meconium-stained amniotic fluid was associated with shorter time to first stool among SSRI-exposed neonates but not in unexposed neonates. The overall model explained a limited proportion of variance. Conclusions Prenatal SSRI exposure was associated with modest but consistent reduction in time to first stool, without affecting time to first void. While the clinical significance remains uncertain, these findings suggest a potential influence of in utero SSRI exposure on early neonatal gastrointestinal adaptation, which may be influenced by intrapartum conditions. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID-19 syndrome share a symptom profile, including severe fatigue, cognitive dysfunction, exertional intolerance, sleep disturbances, hypervigilance, and the paradoxical state of being “wired but tired.” A well-established finding is sympathetic hyperactivity with reduced vagal tone, typically interpreted as autonomic nervous system dysfunction. Emerging evidence, however, suggests a broader disturbance across multiple neurotransmitter systems. This paper reviews current knowledge on neurotransmitter systems implicated in ME/CFS and Long COVID, focusing on potential mechanisms of dysregulation and their roles in disease pathology and symptom generation, as well as implications for treatment. In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported. Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain. A shift favoring excitatory over inhibitory neurotransmission can lead to excessive neural activation, autonomic dysfunction, sensory hypersensitivities, sleep disturbances, and cognitive impairment. Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance, and post-exertional malaise. Various pharmacological treatments may partially rebalance these neurotransmitter systems, but limited efficacy highlights the need for systematic investigation and individualized strategies. Full article

Fibromyalgia (FM) is a complex chronic syndrome marked by widespread musculoskeletal pain, neurocognitive dysfunction (“fibro-fog”), and autonomic disturbances. Clinical management remains challenging due to subjective symptom reporting and the lack of definitive diagnostics. Emerging evidence points to a multifactorial origin involving central sensitization, neuroendocrine imbalance, and systemic immune-inflammatory alterations. A wide array of candidate biomarkers has been reported in FM, encompassing neurotransmitters (serotonin, norepinephrine), excitatory and inhibitory amino acids, metabolic and glycolytic enzymes, stress-related proteins, autoantibodies, oxidative stress markers and pro-inflammatory cytokines. This molecular heterogeneity reflects the systemic and multidimensional nature of FM. However, most of these biomarkers have been primarily investigated in serum or plasma, where analytical validation and reference ranges are more established. In contrast, the exploration of salivary biomarkers—although highly attractive due to its non-invasive, stress-free, and repeatable collection—remains comparatively limited. Saliva contains a reduced concentration range of many systemic markers and is strongly influenced by circadian rhythms, stress, flow rate, and oral health conditions. While promising candidates such as α-amylase, cortisol, calgranulins, and selected metabolic enzymes have shown potential in saliva, many proposed FM-related biomarkers lack full analytical validation, standardized protocols, and clinically defined reference intervals in this matrix. In this context, non-invasive electrochemical biosensors represent a transformative technological approach. Advanced electrode architectures incorporating nucleic acid probes, redox reporters, and nanostructured materials offer high sensitivity in low-volume and low-concentration biofluids such as saliva. The integration of multiplexed biomarker panels into portable platforms could enable real-time, longitudinal monitoring of FM pathophysiology, supporting phenotype stratification, personalized therapeutic adjustment, and objective disease activity tracking. Full article

Fibromyalgia (FM) is a chronic pain syndrome characterized by central sensitization and impaired pain modulation, involving dysfunctional descending inhibitory pathways and altered nociceptive processing. These processes contribute to persistent musculoskeletal pain, difficulties with sleep, feelings of depression, and ongoing fatigue. Serotonin and norepinephrine are key mediators of pain control, and evidence indicates that dual reuptake inhibition provides superior analgesia compared to single-pathway approaches. Accordingly, serotonin–norepinephrine reuptake inhibitors (SNRIs), including milnacipran and duloxetine, approved for FM treatment, show favorable efficacy and tolerability compared with tricyclic antidepressants. This integrative literature review aimed to evaluate the impact of SNRIs on musculoskeletal pain, fatigue, depression, and quality of life in patients with FM by analyzing randomized clinical trials (RCTs), identified via PubMed/MEDLINE searches (2015–2025) in English/Portuguese using descriptors: “Fibromyalgia”, “Serotonin and Norepinephrine Reuptake Inhibitors”, “Duloxetine” and “Milnacipran”. From 195 records screened, 18 studies met inclusion criteria (9.2% inclusion rate); duloxetine evaluated in 16 studies (88.9%), milnacipran in 2 (11.1%); SNRIs demonstrated superior efficacy vs. placebo: pain reduction 30–40%, fatigue improvement 25%, quality of life enhancement 20%. SNRIs were overall more effective than placebo but did not achieve high levels of analgesia, underscoring the need for further research on long-term efficacy and comparisons with combination pharmacological and non-pharmacological therapies. SNRIs significantly alleviate musculoskeletal pain (30–50% of patients), fatigue, depression symptoms, and improve quality of life in FM versus placebo. Duloxetine showed superior efficacy for pain/depression; milnacipran excelled in sleep quality. Long-term studies and combination therapies warrant further investigation. Full article

Mental health disorders (MHDs) and acute coronary syndromes (ACSs) demonstrate reciprocal pathophysiological connections with substantial prognostic implications. Despite robust evidence linking MHDs to adverse cardiovascular outcomes, the bidirectional relationship remains inadequately characterized in clinical practice, with limited integration of mental health screening into routine cardiac care pathways. The present narrative review comprehensively presents contemporary data on epidemiology, shared biological mechanisms, clinical consequences, and integrated management strategies across the MHD–ACS continuum. A synthesis of peer-reviewed literature, meta-analyses, observational cohorts, randomized trials, and international guideline documents was performed, focusing on depression, anxiety, post-traumatic stress disorder, bipolar disorder, schizophrenia, and suicidality in relation to ACSs. MHDs are highly prevalent in ACS populations and independently predict increased mortality, major adverse cardiac events, and poorer functional recovery. Shared mechanisms include chronic low-grade inflammation, autonomic imbalance, hypothalamic–pituitary–adrenal axis hyperactivation, platelet hyperreactivity, and endothelial dysfunction. Selective serotonin reuptake inhibitors and cognitive behavioral therapy demonstrate the strongest evidence for treating depression in cardiac populations. Collaborative, stepped-care, and integrated cardiac rehabilitation models consistently improve psychological outcomes, with variable effects on cardiovascular endpoints. MHDs and ACSs form a self-reinforcing clinical continuum. Routine mental health screening and integrated cardio-psychiatric care represent essential components of secondary prevention and long-term outcome optimization. Full article

Sudden Infant Death Syndrome (SIDS) continues to be one of the most challenging and tragic causes of infant mortality in developed countries. While public health interventions have reduced its prevalence, the underlying mechanisms contributing to SIDS remain largely unclear. The biological basis of SIDS is widely believed to be multifactorial in nature, involving inherited genetic vulnerabilities, including mutations in cardiac ion channels and genes associated with brainstem serotonin function, metabolic enzymes, and inflammatory mediators. This review presents a comprehensive analysis of genetic studies relating to SIDS, incorporating recent findings from molecular autopsies, genome-wide association studies and functional assays. It also explores how gene–environment interactions, polygenic risk scores, and multi-omic strategies are reshaping our understanding of this complex condition. The review aims to integrate recent insights from molecular autopsy, genomic profiling, and gene–environment interactions to offer a framework for better risk assessment and the stratification of vulnerable infants who could benefit from targeted clinical and public health interventions. Full article

Background/Objectives: Plant-based supplements are widely used for the management of anxiety, depression, and insomnia. Despite their over-the-counter availability and perceived safety, these products may pose relevant pharmacological and toxicological risks. This narrative review critically evaluates clinical evidence on commonly used herbal preparations, with particular emphasis on herb–drug interactions, adverse effects, and issues related to product adulteration. Methods: Major scientific databases (PubMed, Scopus, and Web of Science) were searched to identify clinical studies evaluating plant-based supplements for mental health and sleep disorders. Data on study design, dosage, efficacy, and adverse events were analyzed, together with regulatory information and reports of product adulteration and quality concerns. Results: Herbal supplements such as Hypericum perforatum, Passiflora incarnata, Valeriana officinalis, Piper methysticum, Withania somnifera, Crocus sativus, and Curcuma longa demonstrated anxiolytic, antidepressant, and sedative effects in clinical studies, with improvements in mood, stress levels, and sleep quality. Proposed mechanisms include modulation of monoaminergic and GABAergic pathways, serotonergic activity, regulation of the hypothalamic–pituitary–adrenal axis, and anti-inflammatory effects. However, clinically relevant risks were identified, including cytochrome P450–mediated drug interactions, excessive sedation, serotonin syndrome, and toxic effects associated with adulterated products, such as hepatotoxicity, cardiovascular events, and neurological disturbances. Conclusions: While plant-based supplements may provide clinically meaningful benefits for anxiety, depression, and insomnia, their use requires careful clinical monitoring due to potential pharmacokinetic and pharmacodynamic interactions and safety concerns. Increased awareness of herb–drug interactions and stricter quality control are essential to optimize therapeutic outcomes and minimize harm. Full article

Burnout syndrome is increasingly recognized as a significant occupational health issue, characterized by emotional exhaustion, depersonalization, and a reduced sense of personal accomplishment. It predominantly arises from chronic work-related stress, but recent research has highlighted the role of genetic and epigenetic factors in determining individual vulnerability to burnout. This review aims to synthesize findings regarding the genetic footprints of burnout, focusing on genes related to stress regulation, including the 5-HTT (serotonin transporter) gene, BDNF (brain-derived neurotrophic factor) gene, and NR3C1 (glucocorticoid receptor) gene. Twin studies reveal that burnout is moderately heritable, with genetic factors accounting for 33–36% of the variability in burnout-related traits, such as emotional exhaustion and performance-based self-esteem. However, burnout risk seems highly driven by non-shared environmental factors, such as work stress, lack of social support, and personal coping mechanisms. Specific genetic polymorphisms in the serotonergic system (5-HTT) and HPA axis genes (NR3C1, FKBP5) have been linked to increased burnout susceptibility, particularly in individuals exposed to chronic job strain or early-life stressful situations. Variations in 5-HTT rs6354 and HTR2A rs6313 are associated with altered stress reactivity, while polymorphisms in NR3C1 and FKBP5 contribute to dysregulation of the HPA axis, which influences cortisol secretion patterns in response to stress. Increased methylation in genes like BDNF and SLC6A4 has been observed in individuals with burnout, suggesting that environmental stressors may lead to lasting changes in gene expression, contributing to the syndrome’s development. Studies on telomere length have shown that burnout is associated with accelerated cellular aging, with individuals exhibiting shorter telomeres, particularly during high-stress periods. These findings hold particular relevance for professionals within the forensic and justice systems, including law enforcement, the judiciary, and forensic experts, who operate under chronic, high-stakes stress. We examine how understanding the biological basis of burnout can inform more objective ‘fitness-for-duty’ evaluations and provide a scientific framework for distinguishing physiological exhaustion from professional negligence in legal contexts. Full article

Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and represent a major source of caregiver burden. Serotonin 5-HT_2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT_2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident–intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT_2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction. Full article

The indole scaffold represents a privileged structural motif in medicinal chemistry, celebrated for its remarkable chemical versatility, biological ubiquity, and clinical relevance. This review provides a comprehensive analysis of the recent research on the indole nucleus, emphasizing its physicochemical properties, reactivity patterns, and capacity to interact with a wide array of biological targets. Found in key endogenous compounds such as serotonin and melatonin, indole serves as a cornerstone in neurochemical signaling, circadian regulation, and chrono-metabolic homeostasis. Beyond its physiological roles, synthetic indole derivatives have shown extensive therapeutic potential across diverse domains, including oncology, infectious diseases, neurodegenerative disorders, immunomodulation, and metabolic syndromes. The review explores structure–activity relationships (SAR), pharmacokinetics, and the molecular mechanisms by which indole-based compounds exert their tremendous effects, that are ranging from enzyme inhibition to receptor modulation. Special focus is given to current clinical applications and emerging strategies for enhancing drug specificity, bioavailability, and safety through indolic frameworks. Additionally, we highlight the translational potential of indole-containing molecules in personalized medicine, underscoring opportunities for future drug discovery. By integrating insights from medicinal chemistry, biochemistry, pharmacology, and clinical science, this review affirms the indole ring’s enduring value as a central scaffold in therapeutic innovation. Full article

Prader–Willi syndrome (PWS) is a rare, multisymptomatic genetic disorder caused by the absence or dysfunction of specific genes on chromosome 15. The genetic abnormality is anticipated to cause a dysfunction of the hypothalamus, which is also central in the regulation of the autonomic nervous system (ANS). Typical symptoms of PWS indicating a hypothalamic dysfunction include muscular hypotonia, poor growth, short stature, and feeding difficulties in infancy, which in early childhood are replaced by hyperphagia, leading to a high risk of obesity. Other characteristics, such as sleep difficulties, altered pain perception, delayed gastric emptying and constipation, blood pressure irregularities and dysregulated stress response, altered temperature regulation, delayed pupillary reaction, and urine retention and incontinence, all indicate a dysfunction of ANS. The ANS is usually divided into three parts: the sympathetic nervous system (SNS), which activates the fight-or-flight response during stress; the parasympathetic nervous system (PNS), which promotes calm and digestion; and the independent enteric nervous system (ENS), which regulates the gastrointestinal tract. Noradrenaline is the main neurotransmitter for the SNS, and acetylcholine for the PNS, while the ENS is regulated mainly by acetylcholine and serotonin. However, the ENS is modulated by both the SNS and the PNS, as well as many neuropeptides. Peptides regulating behavior, metabolism, appetite, and satiety have been extensively studied in PWS. However, studies of the role of neuropeptides in regulating other autonomic functions are limited and remain poorly understood. This review aims to synthesize current evidence from both animal models and human studies to explore potential mechanisms by which neuropeptides may contribute to autonomic dysfunction in individuals with PWS. Full article

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as “susto” (fright) or “espanto” (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract’s effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD₅₀ was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression. Full article

Irritable Bowel Syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting about 11% of the global population and exerting a substantial burden on quality of life and healthcare systems. Despite the emerging interest in this disease, its pathophysiology remains elusive, reflecting the interplay between the brain–gut axis, neuroendocrine dysregulation, immune activation, barrier dysfunction, microbial imbalance, and environmental triggers. Disruptions in the hypothalamic–pituitary–adrenal axis, impaired serotonin signaling, bile acid malabsorption, and altered intestinal permeability collectively result in the emergence of abnormal motility, visceral hypersensitivity, and chronic inflammation. The gut microbiome further modulates these processes by influencing neurotransmitter metabolism, immune responses, and epithelial integrity, positioning it as both a driver of symptoms and a promising therapeutic target. The aim of this review is to synthesize current mechanistic insights into IBS, highlighting the interconnected roles of the brain–gut axis, immune modulation, and microbial dynamics, and to explore how these pathways may be translated into precision medicine approaches. This review integrates molecular, microbial, and neuroimmune perspectives to propose a systems-level understanding of IBS pathophysiology and its implications for precision medicine. By integrating host–microbe interactions, dietary influences, and genetic predispositions, we highlight the mechanistic complexity underlying IBS and the potential for translating these insights into personalized strategies for symptom control and improved quality of life. Full article