Search Results (764)

3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly implicated in motor control, motivation, and reward mechanisms. In the cerebral cortex it participates in attention processes, working memory, long-term memory, etc. DA overproduction or deficits lead to neuronal circuit imbalance that underlies a number of neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, Huntington’s disease (HD), and substance use disorders (SUDs), to name a few. DA regulates neuronal excitability by modulating ion channels, the release of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters, and postsynaptic interactions with glutamate and GABA receptors. Together, these pre- and postsynaptic actions of DA underlie a number of synergistic or antagonistic actions that have important implications for setting membrane potentials, improving the signal-to-noise ratio, and directing the sign of synaptic plasticity. In this review, I will first provide a historical overview of the many studies exploring DA actions in the brain, with particular focus on the striatum. Then, I will emphasize some of the contributions of our laboratory to the understanding of DA modulatory effects from an electrophysiological perspective. Finally, I will discuss the mechanistic and therapeutic implications of DA function and dysfunction. Full article

Brain fatigue is a debilitating condition whose molecular complexity—neurotransmitter imbalance, neuroinflammation, and metabolic failure—has long defied effective intervention. Conventional open-loop neuromodulation offers fixed stimulation, but fatigue fluctuates. Closed-loop neuromodulation, adjusting stimulation in real time, holds real promise. Yet its delivery hinges on a single, unresolved bottleneck: the sensing–decision chain. In this review, we deconstruct closed-loop systems into sensing, decision, and intervention, and argue that the true challenge is not technological but informational—how to integrate fast electrophysiological signals with slow molecular biomarkers (inflammatory cytokines, neurotrophic factors, adenosine) into a unified control framework. We show that a “fast-slow variable” architecture offers a practical path forward: fast signals guide immediate responses, slow variables set baselines and thresholds, and their integration enables predictive, pre-emptive intervention. We also examine the molecular correlates of neuromodulation—synaptic plasticity, anti-inflammatory signaling, and neurotrophic regulation—as the mechanistic foundation for therapeutic effect. Finally, we confront the translational triad of causality, inter-individual variability, and the information–energy–time trade-off. We conclude that realizing effective closed-loop neuromodulation for brain fatigue will require parallel advances in both stimulation hardware—improving spatial targeting, dose precision, and modality versatility—and individualized sensing–decision algorithms capable of reliably translating multi-modal biomarkers into timely, safe interventions. Both areas remain active fronts of development, and neither can be neglected in clinical translation. Full article

Background: Parkinson’s disease (PD) is a chronic, slowly progressive, and irreversible neuropathological disorder characterized by the progressive degeneration of specific neurons responsible for producing neurotransmitters essential for motor control. Although PD primarily affects motor function, various non-motor symptoms commonly emerge during the prodromal phase. These include autonomic dysfunction, cognitive and neurobehavioral disorders, and sensory and sleep abnormalities. Notably, speech and voice alterations, particularly hypokinetic dysarthria, are frequent manifestations. This research presents a methodology to distinguish between individuals with PD and healthy controls using voice signals through speech recognition and machine learning (ML) techniques. A dataset comprising 81 voice samples (41 healthy controls and 40 PD patients) was utilized to extract two types of cepstral features: Mel-frequency cepstral coefficients (MFCCs) and subband-based cepstral coefficients (SBCs). These extracted features were used to train and evaluate three ML algorithms: Random Forest (RF), K-Nearest Neighbors (KNN), and Support Vector Machines (SVM). Results: Among the algorithms evaluated, the SVM-SBC model exhibited the highest performance, achieving an accuracy of 79%, a sensitivity of 75.5%, and an Area Under the ROC Curve (AUC-ROC) of 84%. Conclusions: This study highlights the potential of integrating cepstral features with machine learning algorithms to develop reliable, non-invasive tools for the early detection of PD. Full article

Fractional ionizing radiation (FIR) is a standard cancer therapy but often induces severe central nervous system complications, including cognitive decline and physiological dysfunction. While natural flavonoids hold therapeutic promise for radiation-induced brain injury (RIBI), optimizing their combinations and elucidating the underlying molecular pathways remain challenging. Methods: To develop a precise therapeutic strategy, we first integrated network pharmacology and UHPLC-Q-Orbitrap MS/MS analysis to identify three highly effective flavonoid monomers from a radioprotective botanical extract. Subsequently, an in vivo anti-inflammatory screening was conducted to determine the optimal combinatorial ratio, designated as the ternary formulation QLI. The neuroprotective efficacy of QLI was then systematically evaluated in a mouse model of fractional RIBI (cumulative dose of 12 Gy) through behavioral assessments, hematopoietic profiling, and neurotransmitter analyses. Transcriptomic alterations were explored via RNA-sequencing (RNA-seq) and validated by molecular docking, RT-qPCR, and Western blotting. Results: Pharmacological and mass spectrometry analyses identified Quercetin, Luteolin, and Isorhamnetin-3-O-glucoside as the core bioactive monomers. Quantitative synergistic screening established the optimal QLI formulation at a mass ratio of 2:1:1. In vivo, FIR exposure induced severe spatial memory deficits, disrupted neurotransmitter homeostasis, and caused hematopoietic decline. Administration of QLI successfully reversed these physiological and cognitive impairments. Transcriptomic profiling revealed that QLI globally reprogrammed aberrant gene expression, specifically normalizing signaling networks related to the PI3K–Akt pathway, apoptosis, and neuroactive ligand–receptor interactions. Multidimensional validation confirmed that QLI mitigated neuroinflammation, suppressed astrocyte hyperactivation (GFAP), and preserved synaptic plasticity by preventing the pathological accumulation of SynGAP and autophagic stress (Beclin-1). Conclusions: The rationally designed ternary flavonoid formulation (QLI) provides potent neuroprotection against fractional RIBI. By resolving neuroinflammation, alleviating synaptic plasticity suppression, and normalizing stress-induced transcriptomic disruptions, QLI represents a promising multi-target experimental formulation with the potential to mitigate radiotherapy-associated neurological side effects. Full article

Background/Objectives: Ephedrae Herba (EH) is widely used in traditional East Asian medicine, but safety concerns regarding its adverse events remain. This study aimed to investigate EH-associated adverse events using clinical pharmacovigilance data and to perform exploratory in silico analyses to propose potential molecular mechanisms underlying these adverse events. Methods: A disproportionality analysis was performed using individual case safety reports from the Korea Adverse Event Reporting System database. EH-containing products were compared with other herbal medicine products using reporting odds ratios (RORs), proportional reporting ratios, and information components. Network pharmacology identified adverse event-related genes and pathways, and protein–protein interaction networks were constructed. Molecular docking predicted direct adverse event-associated targets of ephedrine and compared mechanisms with control compounds (aconitine and spinosin). Results: Four adverse-event signals were detected in the primary analysis: sleep disorder, dry mouth, insomnia, and palpitations. Sensitivity analysis identified four signals, with three (dry mouth, insomnia, and palpitations) consistent across both analyses; constipation emerged only in the sensitivity analysis. Conclusions: Adverse event-associated network analysis predicted key pathways: Neuroactive ligand–receptor interaction, Pathways of neurodegeneration, and Dopaminergic synapse. Molecular docking predicted that ephedrine may act on downstream signaling mechanisms shared by neurotransmitter systems, including the dopaminergic system, distinct from control compounds. Full article

Background/Objectives: Manganese (Mn) is a neurotoxic trace element whose excessive accumulation in the brain can induce hippocampal damage via oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This study investigated whether honokiol (HNK) and its liposomal nanoformulation (HNK-LNPs) can ameliorate Mn-induced hippocampal neurotoxicity by modulating key antioxidant and mitochondrial regulatory pathways. Methods: Male Wistar rats were subjected to Mn exposure to induce hippocampal neurotoxicity and were treated with HNK or HNK-LNPs. We assessed oxidative status via NRF2/HO-1 signaling, antioxidant defenses (glutathione, GPx, SOD, CAT), and oxidative indices (ROS, MDA). Neuroinflammatory markers (NF-κB, TNF-α, IL-1β, IL-6, Iba-1), mitochondrial respiratory chain function and ATP levels, SIRT1/PGC-1α signaling, and neurotransmitter homeostasis were evaluated. We analyzed apoptosis using Bax, Bcl-2, caspase-3, and cytochrome c, along with histopathological and ultrastructural examination of the hippocampus. Results: Mn exposure was associated with NRF2/HO-1 downregulation, depleted endogenous antioxidants, increased ROS and MDA levels, and increased NF-κB–driven neuroinflammation and microglial Iba-1 expression. Mn was further associated with reduced ATP synthesis, dysregulation of SIRT1/PGC-1α signaling, and disrupted neurotransmitter balance, with a pro-apoptotic shift (elevated Bax, caspase-3, cytochrome c; reduced Bcl-2) and neuronal degeneration. Co-treatment with HNK, and more prominently with HNK-LNPs, was associated with reversing these alterations, restoring antioxidant and mitochondrial pathways, dampening inflammatory cascades, normalizing neurotransmitters, and favoring neuronal survival, with many indices approaching control values and consistently surpassing free HNK. Conclusions: Liposomal encapsulation significantly enhances honokiol’s neuroprotection against Mn-induced hippocampal neurotoxicity, likely via improved CNS bioavailability and coordinated modulation of NRF2/HO-1 and SIRT1/PGC-1α pathways. These findings support HNK-LNPs as a promising multi-mechanistic therapeutic strategy for metal-induced and related neurotoxic brain disorders. Full article

Substance use disorders (SUDs) remain a major public health concern and contribute substantially to compromised quality of life, mortality, and healthcare burden. In the United States alone, millions of individuals are affected by alcohol use disorder (AUD), tobacco use disorder (TUD), and opioid use disorder (OUD), with many cases complicated by co-existing anxiety and stress-related disorders. Piper methysticum G. Forst (kava), a traditional South Pacific plant preparation, has gained attention for its anxiolytic, sedative, and sleep-promoting properties. Its pharmacological effects are primarily attributed to a set of lipophilic compounds known as kavalactones, which have been reported to modulate GABA_A receptor activity, dopaminergic and adrenergic signaling pathways, monoamine oxidase-B activity, cannabinoid receptor type 1 activity, and voltage-gated ion channels. Peer-reviewed literature was identified through searches of PubMed, NIH resources, and other scientific databases using terms related to kava, kavalactones, addiction, anxiety, stress, insomnia, and SUDs. Both clinical and preclinical studies were reviewed, including investigations of neurotransmitter systems and addiction-related signaling pathways. The current literature suggests that the strongest rationale for kava use exists in AUD, where anxiety and stress are established contributors to relapse. Evidence supporting kava use in TUD and OUD is largely theoretical, while concerns regarding hepatotoxicity, cytochrome P450 interactions, product variability, and additive risk remain important barriers to its clinical application. In summary, current evidence does not support kava as a replacement for established therapies, while its unique pharmacological profile warrants further investigation as a potential adjunctive treatment for withdrawal and relapse in SUDs. Full article

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis. Full article

Background/Objectives: Anxiety disorders represent a major global public health challenge, with increasing prevalence and substantial unmet therapeutic needs. Emerging evidence suggests that vitamin D modulates multiple neurobiological pathways involved in anxiety, although the underlying mechanisms remain incompletely understood. This review provides a comprehensive synthesis of experimental and bioinformatics evidence on the anxiolytic effects of vitamin D. Methods: The current literature on the anxiolytic effects of vitamin D in rodent models was critically reviewed, focusing on evidence related to neurotransmitter systems, neuroplasticity, neurotrophic factors, neuroinflammation, oxidative stress, and receptor-mediated signaling. Bioinformatics analyses were incorporated to identify molecular targets and signaling pathways potentially linking vitamin D to anxiety-related mechanisms. Results: The integrated evidence indicates that vitamin D exerts pleiotropic neurobiological effects through the coordinated modulation of neuroinflammatory signaling, neuroplasticity, monoaminergic neurotransmission, neuroendocrine regulation, epigenetic mechanisms, and vitamin D metabolism, all of which are implicated in the pathophysiology of anxiety disorders. Bioinformatics analyses further supported these findings by identifying molecular targets and signaling pathways potentially involved in the anxiolytic effects of vitamin D. Conclusions: Current evidence supports a potential role for vitamin D in anxiety disorders, but further translational and clinical studies are required to establish its therapeutic value. Full article

Neurotoxicity is generally thought to result from exogenous agents like environmental chemicals, drugs and biological toxins. However, increasing evidence suggests that many endogenous molecules that play a critical role in normal brain function can become neurotoxic when the regulatory mechanism involved in their production, metabolism, compartmentalization and clearance are disrupted. This shift underlies the basis of endogenous neurotoxicity. This review discusses the major endogenous sources of neurotoxicity: metabolic neurotoxins, dysfunctional neurotransmitters, protein aggregates and inflammatory mediators. These endogenous factors arise from different physiological pathways, but share common pathogenic mechanisms, all of which involve an underlying state of oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxic signalling, neurovascular dysfunction and maladaptive neuroglial responses. This is not a singular process but a network of interconnected processes, which work together to progressively diminish neuronal resilience and promote synaptic dysfunction and neurodegeneration. The review also underscores the critical role of astrocytes, microglia and other glial cells in the maintenance of neuronal homeostasis. By integrating diverse endogenous neurotoxic pathways within a unified homeostasis-centred framework, this review provides a broader perspective on the mechanisms linking metabolic disorders, aging and neurodegenerative diseases. This framework suggests that effective therapeutic strategies may require restoration of physiological regulatory networks rather than targeting individual neurotoxic molecules in isolation. A systems-level understanding of endogenous neurotoxicity may therefore facilitate the development of earlier biomarkers and more effective interventions aimed at preserving neuronal homeostasis and preventing progressive neurological dysfunction. Full article

Non-surgical aesthetic procedures, including energy-based devices and injectable therapies, have become increasingly popular worldwide, creating distinct skincare needs for peri-procedural recovery and long-term post-procedure maintenance. This narrative review summarizes current evidence on cosmetic peptides as adjunctive skincare across both phases. A structured literature search was conducted in PubMed, Embase, and Google Scholar, only including peptides with an International Nomenclature of Cosmetic Ingredients (INCI) designation and defined amino acid sequences. Available clinical evidence suggests potential roles for cosmetic peptides in two interconnected scenarios. In peri-procedural care—spanning pre-procedure conditioning through post-procedure recovery—signal peptides, carrier peptides, and antimicrobial peptides have demonstrated benefits in accelerating healing and reducing erythema, edema, and bruising. As a long-term adjuvant strategy, signal peptides, neurotransmitter-inhibiting peptides, and whitening peptides may contribute to collagen remodeling, wrinkle reduction, and pigment control. Although enzyme-inhibiting peptides currently lack direct clinical evidence, their proposed mechanisms suggest potential for future investigation. However, the evidence remains limited by small sample sizes, short follow-up periods, heterogeneous peptide formulations and treatment protocols, and frequent use of proprietary multi-ingredient products. Overall, cosmetic peptides represent a potential adjunctive approach in aesthetic medicine. Larger, well-designed randomized controlled trials are needed to establish their clinical value and long-term safety. Full article

Peripheral γ-aminobutyric acid (GABA) signaling is emerging as a context-dependent contributor to metabolic regulation. Long recognized as the principal inhibitory neurotransmitter in the central nervous system, GABA’s role as an important signal in peripheral tissues is recently getting attention. This expanded view raises a central question: why do GABA-sensitive pathways support regulation in some metabolic settings, yet reinforce dysfunction in others? In obesity and type 2 diabetes mellitus (T2DM), nutrient excess, insulin resistance, and chronic inflammation remodel the cellular environments in which GABA is produced, sensed, and metabolized. As a result, GABA signaling may shift from adaptive regulation that maintains tissue function to compensatory responses that attempt to limit metabolic stress, and ultimately to maladaptive outputs that reinforce disease progression. Here, we review the biochemical basis, sources, receptor systems, and extracellular regulation of peripheral GABA signaling. We then examine how GABA-sensitive pathways are organized across metabolic tissues and remodeled in obesity and T2DM, with emphasis on islet endocrine dysfunction, hepatic GABA output, and adipose–immune–microbiota interactions. We further consider how this framework informs pathway-specific therapeutic strategies and the barriers to translation. We propose that peripheral GABA signaling is neither inherently protective nor harmful. Its metabolic consequence depends on the source of GABA, the responding tissue environment, and the stage of metabolic disease. Full article

Mating influences the physiology of female animals and induces changes in behaviors associated with securing resources for their offspring. Modulatory neurotransmitters are known to adjust behavioral responses of animals according to environmental cues and internal physiological states. In that regard, it has been shown that serotonin (5-HT) modulates some post-mating behavioral features in Drosophila. However, it remains unknown whether serotonin regulates post-mating social behavior or responses to food cues in flies, which are among several behaviors that serve to secure their survival and reproduction. Here, we report a behavioral paradigm, the yeast-response test (YRT), for exploring locomotor and social behavioral changes in groups of virgin and mated females using yeast odor as a naturalistic food signal. Using this setup, we found that exposure to yeast odor increases social interactions in mated but not virgin females under non-aversive conditions and that these responses are suppressed at aversive temperatures. Furthermore, chronic impairment of serotonin transporter function reverses the social behavioral response to food odor in mated females, without affecting their olfactory capacity. Whole-brain 5-HT content, as well as histone serotonylation, were unchanged between virgin and mated females, suggesting that 5-HT contribution to these changes is mediated at a circuit level rather than by global neuromodulatory mechanisms. Consistent with this idea, silencing serotonin projection neurons (SPNs) selectively abolished mating-induced changes in social behavior without affecting the locomotor effects. These results provide further support for data in the literature showing that SPNs belong to a discrete circuit underlying social behaviors in female flies. Together, these results support a model in which serotonergic signaling shapes post-mating behavior in Drosophila through functionally segregated neural circuits. Full article

A marked reduction in estrogen levels during perimenopause substantially elevates the risk of Alzheimer’s disease (AD) and cognitive dysfunction in women. While the endocrine etiology is well established, applying this understanding to effective clinical prevention remains difficult. Recent findings of diminished cerebral glucose metabolism and lower mitochondrial cytochrome oxidase activity in menopausal women have shifted research attention toward mitochondrial homeostasis disruption and neuroimmune–inflammatory network imbalance as central mechanisms underlying menopausal cognitive decline. This article examines the characteristics and underlying mechanisms of mitochondrial and immune imbalances induced by estrogen withdrawal during menopause. Estrogen deficiency is shown to disrupt mitochondrial–immune homeostasis, particularly via ERβ-mediated mitochondrial oxidative phosphorylation system (OXPHOS) dysfunction and subsequent excessive activation of the NLRP3 inflammasome. The analysis further addresses enhanced inflammatory signaling resulting from excessive reactive oxygen species generation and mitochondrial DNA (mtDNA) release, as well as reduced synaptic plasticity due to impaired neurotransmitter synthesis and an inflammatory microenvironment. Additionally, the dysregulation of the estrogen-neuromodulatory system in menopausal cognitive decline is investigated. Recent studies demonstrate that intervention strategies targeting estrogen receptors, especially selective ERβ agonists, possess significant neuroprotective potential. Future approaches should incorporate biomarkers, including neuroimaging and genetic polymorphisms, to facilitate risk-stratified and individualized precision medicine. This integration may enhance the prevention or delay of menopause-associated cognitive decline in women. Full article

Beyond its canonical role as the principal inhibitory neurotransmitter in the central nervous system (CNS), peripheral GABAergic signaling has emerged as an important regulator of skin barrier immunity and tissue homeostasis. This review synthesizes current evidence on the expression, distribution, and function of both GABA-A and GABA-B receptors in keratinocytes, fibroblasts, melanocytes, sensory neurons, and cutaneous immune cells, including Langerhans cells, macrophages, mast cells, and T lymphocytes. Particular emphasis is placed on how GABAergic signaling regulates ion transport, calcium dynamics, epidermal differentiation, and immune homeostasis through coordinated interactions with ion channels within the broader cutaneous neuro-immuno-endocrine network. We further discuss evidence supporting the role of cutaneous GABAergic signaling in maintaining barrier integrity, modulating inflammatory responses, and contributing to skin–brain communication within the broader cutaneous neuro-immuno-endocrine network under physiological and pathological conditions. Finally, we summarize the therapeutic potential of targeting peripheral GABAergic pathways in atopic dermatitis, psoriasis, chronic pruritus, photoaging, and other stress-associated dermatoses, highlighting their promise as novel therapeutic strategies in precision dermatology. Full article