Search Results (129)

Treatment-resistant depression (TRD) affects 20–30% of patients with major depressive disorder and presents a significant clinical challenge due to its biological diversity. This review highlights standard mechanisms that contribute to treatment resistance beyond traditional monoaminergic models. Evidence supports serotonergic dysregulation, including 5-HT1A autoreceptor dysfunction and “serotonin flooding” as well as dopaminergic deficits linked to anhedonia and an imbalance between glutamate and GABA that impair synaptic plasticity. Changes in neurotrophic signaling, such as reduced BDNF and VEGF activity, complicate recovery by limiting neural repair and regeneration. Chronic inflammation and oxidative stress contribute to neuronal dysfunction, while HPA axis dysregulation may exacerbate depressive symptoms and resistance to antidepressants. Emerging evidence suggests that obesity and gut microbiota imbalance reduce the production of short-chain fatty acids by bacteria and increase intestinal permeability, thereby influencing neuroinflammatory and neurochemical processes in TRD. Neuroimaging studies reveal hyperconnectivity within the default mode network and impaired reward circuits, both of which are associated with persistent symptoms and a poor treatment response. By combining evidence on inflammation, oxidative stress, neuroendocrine disturbances, microbiome changes, and brain connectivity issues, this review develops a comprehensive framework for understanding TRD. It emphasizes the importance of biomarker-based subtyping to guide personalized future treatments. Full article

Background/Objectives: The gut microbiome is increasingly recognized as a key modulator of central nervous system function through the gut–brain axis. Dysbiosis has been associated with neuropsychiatric disorders such as depression, anxiety, impulsivity, cognitive decline, and addiction. This review aims to synthesize mechanistic insights and therapeutic perspectives on how gut microbiota influence mood regulation, decision-making, and cognitive processes. Methods: A comprehensive narrative review was conducted using peer-reviewed articles retrieved from PubMed, Scopus, and Web of Science up to August 2025. Studies were included if they explored microbiota-related effects on behavior, mood, cognition, or decision-making using human or animal models. Emphasis was placed on molecular mechanisms, microbiome-targeted therapies, and multi-omics approaches. Results: Evidence indicates that gut microbiota modulate neurochemical pathways involving serotonin, dopamine, GABA, and glutamate, as well as immune and endocrine axes. Microbial imbalance contributes to low-grade systemic inflammation, impaired neuroplasticity, and altered stress responses, all of which are linked to mood and cognitive disturbances. Specific microbial taxa, dietary patterns, and interventions such as probiotics, prebiotics, psychobiotics, and fecal microbiota transplantation (FMT) have shown promise in modulating these outcomes. The review highlights methodological advances including germ-free models, metagenomic profiling, and neuroimaging studies that clarify causal pathways. Conclusions: Gut microbiota play a foundational role in shaping emotional and cognitive functions through complex neuroimmune and neuroendocrine mechanisms. Microbiome-based interventions represent a promising frontier in neuropsychiatric care, although further translational research is needed to define optimal therapeutic strategies and address individual variability. Full article

The autonomic nervous system (ANS) regulates internal organ function to maintain homeostasis. Dysautonomias are ANS disorders involving reduced or excessive sympathetic or parasympathetic activity and can be associated with metabolic syndrome and eating disorders such as binge eating disorder (BED). The ANS exhibits synaptic plasticity phenomena, including long-term potentiation (LTP) and neurotransmitter expression changes, which may influence autonomic function. BED is defined as recurrent, compulsive intake of large amounts of high-calorie food in a short time. Here, we examined dysautonomia in a rat BED model induced by cycles of food restriction and access to highly caloric food, and assessed whether exercise prevents these alterations. After confirming BED induction, we characterized LTP in the superior cervical ganglion (SCG) and analyzed acetylcholine (ACh) and GABA expression and their co-localization/segregation. BED rats exhibited impaired LTP and increased GABA expression. Voluntary aerobic exercise prevented BED onset and the associated changes in LTP and GABA. We propose that BED-associated dysautonomia proceeds at least in the ganglionic sympathetic cholinergic transmission, with reduced sympathetic activity. These results may contribute to a better understanding of the autonomic disorder associated with BED and support exercise as a protective intervention. Full article

Background/Objectives: Polygonatum sibiricum (PS), possessing both medicinal and edible dual functions, boasts a long history of application in Chinese traditional practices. As a component of its effectiveness, Polygonatum sibiricum polysaccharides (PSPs) have been reported to exert neuroprotective effects. However, the protective effects of PS on the cognitive deficits induced by simulated weightlessness remain unclear. This study evaluated the therapeutic potential of PSPs to counteract the cognitive deficits induced by simulated weightlessness using the Hindlimb Unloading (HU) method. Methods: Mice were subjected to HU to establish cognitive impairment, and PSP was administered for four weeks. The Morris water maze test (MWMT) and passive avoidance test (PAT) were used to evaluate the cognitive abilities of mice, followed by an analysis of molecular mechanisms. Results: PSP treatment increased learning and memory in mice. PSP treatment partially restored gut microbial diversity and composition towards beneficial taxa, including Lactobacillus and Firmicutes, while inhibiting proinflammatory genera, including Alistipes and Proteus. At the same time, PSP upregulated Claudin-5 and Zonula Occludens-1 (ZO-1) levels in the colon, suggesting improved intestinal barrier integrity, and decreased neuroinflammatory response by inhibiting NLRP3 inflammasome activation and NF-κB phosphorylation in the hippocampus. It also modulated neurotransmitter homeostasis along the microbiota–gut–brain (MGB) axis by increasing the levels of gamma-aminobutyric acid (GABA) and serotonin (5-HT) while reducing the levels of excitotoxic metabolites, including Glutamate (Glu) and 3-hydroxykynurenine (3-HK). Conclusions: These results indicate that PSP may have beneficial effects on HU-induced cognitive impairment by regulating gut microbiota, enhancing barrier function, suppressing neuroimmune signaling, and restoring neurotransmitter balance. Full article

This review explores links between the gut–brain axis, probiotics, and Alzheimer’s disease (AD). Using PRISMA-aligned methods, we examined literature from PubMed, ClinicalTrials.gov, and Google Scholar. Studies show that probiotics may reduce AD symptoms by modulating neuroinflammation, microbial composition, and neurotransmitter signaling. Probiotic strains such as B. breve and L. plantarum were found to be beneficial in early AD or mild cognitive impairment. Limitations include short intervention periods and strain variability. Clinical guidelines and research recommendations are discussed. Mechanisms involve immune signaling, neurotransmitter synthesis (GABA and serotonin), and modulation of systemic inflammation. Full article

The growing prevalence of mental health issues and cognitive impairment poses a significant challenge to global public health. Conditions such as depression, anxiety, neurodegenerative diseases, and stress-related cognitive dysfunction are becoming more common, while conventional pharmacotherapies are often limited by suboptimal efficacy, adverse side effects, and concerns about long-term use. Against this backdrop, neurophytochemistry—the study of plant-derived bioactive compounds—has emerged as a promising area of research. This review explores the potential of selected phytochemicals to support mental well-being and cognitive function via various molecular mechanisms. Compounds such as apigenin, hesperidin, and epigallocatechin gallate have been shown to have a significant impact on key regulatory pathways. These include enhancing neurogenesis via brain-derived neurotrophic factor, modulating neurotransmitter systems (such as GABA and serotonin), and attenuating oxidative stress and neuroinflammation. The therapeutic relevance of these compounds is discussed in the context of depression, anxiety, Alzheimer’s disease, Parkinson’s disease, and stress-related cognitive dysfunction, often referred to as ‘brain fog’. This review synthesizes evidence published between 2010 and 2025 from several scientific databases, including PubMed, Scopus, Web of Science, and Embase. Preliminary evidence from in vitro studies and animal models indicates that neurophytochemicals could enhance synaptic plasticity, protect neurons from oxidative damage, and modulate inflammatory pathways, particularly those involving NF-κB and the Nrf2/ARE antioxidant response. In addition, early human clinical trials have shown that phytochemical supplementation can lead to improvements in mood regulation, stress response, and cognitive performance. Furthermore, emerging evidence suggests that the gut–brain axis plays a key role in mediating the effects of phytochemicals. Several compounds have been found to modulate the composition of gut microbiota in ways that could enhance the function of the central nervous system. While the initial results are encouraging, more high-quality clinical trials and mechanistic studies are required to validate these findings, optimize dosage regimens, and guarantee the safety and efficacy of long-term use. Thus, neurophytochemicals represent a promising integrative approach to alleviating the increasing burden of mental and cognitive disorders through naturally derived therapeutic strategies. Full article

In this paper, we aimed to evaluate the efficacy and usefulness of three brief, easy-to-administer, and repeatable tests, namely SDMT, Digit Span Forward (DSF), and Digit Span Backward (DSB) in MS patients (MSp), and compared the results with those of healthy volunteers (CONs). We were hoping to identify the most sensitive test that could be used regularly in clinical practice. In addition, we tried to identify the metabolic background of the cognitive setting using the advanced radiological method, Mescher–Garwood (MEGA)-edited 1H Magnetic Resonance Spectroscopy (1H-MRS). A total of 22 relapsing MSp and 22 CONs were enrolled. The SDMT, DSF, and DSB tests were used on all participants. The patients also underwent a 1H-MRS brain examination. In addition to N-Acetyl-Aspartate (tNAA), Myoinositol (mIns), Choline (tCho), and Creatine (tCr) were also evaluated GABA and Glutamate–Glutamine (Glx) ratios. CONs were superior to MSp in the results of all neurocognitive tests. The DSB was found to be the most sensitive test for identifying MSp. The SDMT in MSp correlated with inflammatory and degenerative metabolites in the thalamus, hippocampus, and corpus callosum. A correlation between increased Glx- and GABA-ratios and SDMT was found. Unlike the SDMT, the DSF and DSB showed correlations with inflammatory metabolites in the caudate nucleus and hypothalamus. DSF correlated with GABA ratios in the hippocampus. Our study confirms the efficacy of DSF and DSB tests in evaluating working memory cognitive impairment in MSp, showing an association of the tests with specific brain metabolites. Full article

Background and Objectives: Methamphetamine (METH) is a potent psychostimulant known to induce neurotoxicity and neurodegeneration, leading to cognitive impairment. This study aimed to explore cubebin’s potential neuroprotective effects against METH-induced cognitive deficits by investigating its ability to suppress lipid peroxidation and pro-inflammatory markers and modulate neurotransmitter levels. Material and Methods: A total of 30 rats were taken and randomly grouped into five groups: group I—control; group II—METH 100 mg/kg/i.p.; group III—METH + cubebin (10 mg/kg/p.o.); group IV—METH + cubebin (20 mg/kg/p.o.); and group V—cubebin per os at 20 mg/kg. After a 14-day oral regimen, behavioral activities were assessed utilizing the Morris water maze (MWM). Biochemical analysis included neurotransmitters, including dopamine (DA), norepinephrine (NE), and gamma-aminobutyric acid (GABA); oxidative stress markers (malondialdehyde (MDA); nitric oxide (NO), catalase (CAT), reduced glutathione (GSH)); inflammatory cytokines [interleukin (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)]; neurotrophic factors (BDNF, CREB); and apoptotic markers (caspase-3 and caspase-9). Furthermore, molecular docking and simulation studies were conducted. Results: Treatment with cubebin led to a marked reduction in latency during the MWM task. It significantly modulated the oxidative stress markers (SOD, GSH, CAT, MDA, and NO), inflammatory cytokines (IL-6, IL-1β, TNF-α), neurotrophic factors (CREB, BDNF), apoptotic markers (NFkB, caspase-3, caspase-9), and neurotransmitters (NE, DA, and GABA) in METH-induced memory-impaired rats. The results of molecular dynamics simulation (MDS) provided insight into the mechanisms that associate proteins CREB, BDNF, and caspase-3 in conformational dynamics upon binding to cubebin. Conclusions: In conclusion, cubebin administration improved cognitive function in rats by modulating antioxidant enzyme activity, reducing pro-inflammatory cytokines, and regulating neurotransmitter levels, demonstrating its potential neuroprotective effects against MA-induced neurodegeneration. Full article

Lead (Pb) and cadmium (Cd) severely impair rice growth, yield, and grain quality. This study assessed the role of exogenous gamma-aminobutyric acid (GABA) in mitigating Pb and Cd toxicity in aromatic rice ‘Guixiangzhan’. Treatments included the control (no Pb, Cd, or GABA), GABA (1 mM), Pb (800 mg/kg of soil)+GABA, Cd (75 mg/kg of soil)+GABA, Pb+Cd+GABA, Pb, Cd, and Pb+Cd without GABA. GABA improved chlorophyll and carotenoid, protein, proline and GABA contents whilst reducing oxidative stress under Pb/Cd toxicity. GABA application regulated antioxidant enzyme activities, net photosynthesis, and gas exchange, while its effects on nitrate reductase and glutamine synthetase were variable. Compared with Pb+Cd, the grain yields were 34.03%, 31.94%, 15.88%, 24.86%, and 17.32% higher in (Pb, Cd, Pb+Cd)+GABA, Pb, and Cd treatments, respectively. Furthermore, GABA reduced Pb and Cd accumulation in aboveground parts, while Ca, Mg, Fe, Cu, Zn, and Mn levels varied across treatments. Cd translocation was more from root-to-leaves, while Pb translocation was more from leaves-to-grains. Grain Pb and Cd positively correlated with their root, stem, and leaf contents but negatively with mineral nutrients. Overall, exogenous GABA mitigated Pb and Cd toxicity in aromatic rice. 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

Botulinum neurotoxins (BoNTs) are known to inhibit synaptic transmission by targeting SNARE proteins, but their selectivity toward central excitatory and inhibitory pathways is not yet fully understood. In this study, the interaction of serotypes A (BoNT/A) and B (BoNT/B) with the glutamatergic and GABAergic systems has been investigated using a pharmacological approach in an animal model of inflammatory pain, i.e., the formalin test in mice. BoNTs were administered intracerebroventricularly, three days before testing, followed 15 min before testing by systemic administration of sub-analgesic doses of MK801, an NMDA receptor antagonist, or muscimol, a GABA_A receptor agonist. BoNT/A reduced the second phase of the formalin test without affecting both the first phase and the interphase, suggesting a selective action on excitatory glutamatergic circuits while sparing GABAergic inhibition. Co-administration of MK801 with BoNT/A did not enhance analgesia, and muscimol did not further reduce interphase, confirming preserved GABAergic transmission. In contrast, BoNT/B abolished the interphase, consistent with impaired GABA release. Co-administration of MK801 or muscimol with BoNT/B restored the interphase, indicating compensatory rebalancing of excitatory-inhibitory networks. These results demonstrate that BoNT/A and BoNT/B exert distinct effects on central neurotransmission and support the hypothesis that BoNT/A preferentially targets excitatory synapses, while BoNT/B targets inhibitory synapses. This work contributes to a deeper understanding of anti-inflammatory mechanisms of BoNTs and their selective interaction with central pain pathways. Full article

Sensory dysregulation represents a core challenge in autism spectrum disorder (ASD), affecting perception, behavior, and adaptive functioning. The brain’s ability to reorganize, known as neuroplasticity, serves as the basic principle for therapeutic interventions targeting these deficits. Neuroanatomical mechanisms include altered connectivity in the sensory and visual cortices, as well as in the limbic system and amygdala, while imbalances of neurotransmitters, in particular glutamate and gamma-aminobutyric acid (GABA), contribute to atypical sensory processing. Traditional therapies used in sensory integration are based on the principles of neuroplasticity. Increasingly, new treatments use this knowledge, and modern therapies such as neurofeedback, transcranial stimulation, and immersive virtual environments are promising in modulating neuronal circuits. However, further research is needed to optimize interventions and confirm long-term effectiveness. This review discusses the role of neuroplasticity in the etiopathogenesis of sensory integration deficits in autism spectrum disorder. The neuroanatomical and neurotransmitter basis of impaired perception of sensory stimuli is considered, and traditional and recent therapies for sensory integration are discussed. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

Research into the potential health consequences of trauma indicates that traumatic experiences can disrupt normal biological processes and increase the risk of neuroinflammation and the development of clinical symptoms of post-traumatic stress disorder (PTSD). In this study, we examined the relationship between neuroinflammation and three specific biomarkers—matrix metalloproteinases MMP-2 and MMP-9, the inflammasome NLRP3, and the inhibitory neurotransmitter GABA—in connection with PTSD symptoms assessed using the PTSD Symptom Scale–Interview for DSM-5 (PSSI-5). The symptoms were categorized into the following domains: re-experiencing, avoidance, alterations in cognition and mood, increased arousal and reactivity, distress and functional impairment, symptom onset and duration, and the total symptom score. Our findings confirmed the pro-inflammatory roles of MMP-2, MMP-9, and the inflammasome NLRP3, as well as the anti-inflammatory, calming effect of GABA. We identified strong correlations between biomarkers, particularly between MMP-2 and MMP-9, MMP-2 and NLRP3, and MMP-2 and GABA, highlighting a closely interconnected inflammatory response. Among the PSSI-5 domains, re-experiencing, increased arousal and reactivity, and distress and functional impairment showed the strongest associations with the total symptom score. Recent research focusing on these cellular mechanisms has provided valuable insights into the role of neuroinflammation in PTSD. These findings enhance our understanding of how inflammation contributes to the disorder’s development and progression. Full article

Anxiety disorders are among the most common psychiatric conditions that significantly impair one’s quality of life and place a significant burden on healthcare systems. Conventional treatments have certain restraints, such as potential side effects and limited efficacy. Τhe underlying pathophysiological mechanisms of anxiety are not fully understood. A comprehensive literature search was performed in MEDLINE and Scopus databases for original English-language articles published between January 2014 and December 2024. Study selection, data extraction, and screening were independently carried out by multiple investigators using predefined criteria. Our review aimed to help better comprehend the molecular basis of anxiety, focusing on the hypothalamic–pituitary–adrenal (HPA) axis, serotonergic signaling, and gamma-aminobutyric acid (GABA) neurotransmission. In addition, we addressed the role of epigenetics and pharmacogenomics in personalized treatment. Although novel anxiety treatments are promising, they are predominantly preclinical and highly heterogeneous, which poses a challenge to achieving reliable therapeutic efficacy. Our findings could potentially contribute to the development of new therapeutic interventions. Further research is warranted, especially in human subjects, with an aim to combine genetic and epigenetic profiles to refine treatment approaches and develop innovative therapeutics. Full article