Search Results (160)

Background: Multiple studies of the role of neurotransmitter systems in the effects of various substances on brain functions under normal conditions and at various brain disorders have demonstrated the relatively high usefulness of the electroencephalogram (EEG). However, little is known about EEG “fingerprints” of direct neurotransmitter–receptor interactions, in particular, for monoamine (MA) systems involved in the main brain functions. Methods: We looked at how the EEG effects of serotonin, dopamine, and norepinephrine receptors activating substances (quipazine, SKF-38393, and clonidine, respectively) injected into the brain’s lateral ventricles were affected by corresponding blockers (cyproheptadine, SCH-23390, and yohimbine) in freely moving rats. We introduced a method for clustering significant changes in the EEG spectra based on specific time intervals and narrow frequency subranges. Results: Stimulating serotonin and dopamine receptors caused specific suppression of EEG activity around 10 Hz and an increase near 18 Hz, respectively. The effects were reduced after pretreatment with the corresponding receptor blockers. Clonidine produced clusters of increased and decreased EEG activity around 6 Hz and 21 Hz, respectively, which were weakened by the blocker, yohimbine. These results demonstrate the “signatures” of different MA systems in EEG time–frequency clustering. Conclusions: We consider the developed approach as a potentially useful tool in clinics for evaluation of MA transmission pathology and its therapy with corresponding substances penetrating the blood–brain barrier. Full article

Depression is a common mental disorder with high economic burden, characterized by high disability and mortality rates. The etiology of depression remains unclear to date, and there are various hypotheses regarding the pathogenesis of depression in clinical practice, including the monoamine neurotransmitter hypothesis, the hypothalamic–pituitary–adrenal (HPA) axis dysregulation hypothesis, the inflammatory cytokine hypothesis, and the neurotrophic factor hypothesis. These theories offer specific directional aid in the clinical management of individuals suffering from depression. Medicinal intervention stands as a critical approach within the spectrum of depression treatments, and this article reviews the specific mechanisms of different hypotheses on the pathogenesis of depression in recent years, as well as the research progress on related therapeutic drugs. Full article

Heavy metals are a major toxicological concern due to their adverse effects on human health, particularly in children exposed to contaminated areas. This study evaluated biomarkers of exposure in 253 children aged 6 to 12 from Magangue, Achi, and Arjona (Bolivar, Colombia), analyzing their relationship with neurotoxicity and hematological markers. The mean Pb concentrations at the study sites were 1.98 µg/g (Magangue) > 1.51 µg/g (Achi) > 1.24 µg/g (Arjona). A similar pattern was observed for Cd concentrations for Magangue (0.39 µg/g) > Achi (0.36 µg/g) > Arjona (0.14 µg/g). In contrast, Se concentrations followed a different trend for Arjona (0.29 µg/g) > Magangue (0.21 µg/g) > Achi (0.16 µg/g). The proportion of Se/Pb molar ratios > 1 was higher in Arjona (3.8%) than in Magangue (0.9%) and Achi (2.0%). For Se/Cd ratios, values > 1 were also more frequent in Arjona (70.7%), exceeding 20% in the other two locations. Significant differences were found among locations in red and white blood cell parameters and platelet indices. Neurotransmitter-related biomarkers, including serotonin, monoamine oxidase A (MAO-A), and acetylcholinesterase levels, also varied by location. Principal component analysis showed that Pb and Cd had high loadings on the same component as PLT, WBC, and RDW, and while Se loaded together with HGB, PDW, MCHC, MCH, and MCV, suggesting distinct hematological patterns associated with each element. Multiple linear regression analysis demonstrated a statistically significant inverse association between hair Pb levels and serotonin concentrations. Although MAO-A and Cd showed negative β coefficients, these associations were not statistically significant after adjustment. These findings highlight the potential impact of toxic element exposure on key hematological and neurochemical parameters in children, suggesting early biological alterations that may compromise health and neurodevelopment. Full article

Alzheimer’s disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure–activity relationships, and their interactions with the molecular targets at the molecular level. Full article

Electroanalysis of monoamine neurotransmitters is a useful tool for monitoring relevant neurodegenerative disorders and diseases. Electroanalysis of neurotransmitters using analytical devices consisting of electrodes modified with tailored and nanostructured composite materials is an active research topic nowadays. Nano- and microstructured composite materials composed of various organic conductive polymers, metal/metal oxide nanoparticles, and carbonaceous materials enable an increase in the performance of electroanalytical sensing devices. Synergistic properties resulting from the combination of various pristine nanomaterials have enabled faster kinetics and increased overall performance. Herein, recent results related to the design and elaboration of electroanalytical sensing devices based on cost-effective and reliable nano- and microstructured composite materials for the quantification of monoamine neurotransmitters are presented. The discussion focuses on the fabrication procedures and detection strategies, highlighting the capabilities of the analytical platforms used in the determination of relevant analytes. The review aims to present the main benefits of using composite nanostructured materials in the electroanalysis of monoamine neurotransmitters. Full article

Due to the roles of oxidative stress, inflammation, and neurotransmitter imbalances in cognitive and mental dysfunction, we aimed to develop a functional drink with antioxidant and anti-inflammatory properties as well as the potential to support neurotransmitter balance for improved cognition and mental health. The Teng Mo, Fen Hong Mee, and Hong Chon Su guava varieties were screened for their polyphenol and flavonoid contents, antioxidant and anti-inflammatory effects, and suppressive effects on acetylcholinesterase (AChE), monoamine oxidase (MAO), GABA transaminase (GABA-T), and glutamate decarboxylase (GAD). Juice from the cultivar with the highest potential was selected and mixed with mint and honey syrups, pomelo-derived dietary fiber, ascorbic acid, agar, water, and fruit puree (pear/apple/orange) to create three guava jelly drink formulations. The formulation with pear puree showed the highest biological potential and was selected as the final product. It is rich in vitamin C, gallic acid, and dietary fiber, and provides approximately 37 Kcal/100 g. It also promotes the growth of lactic acid-producing bacteria in the culture. Thus, our drink shows the potential to reduce oxidative stress and inflammation, improve neurotransmitter regulation, and stimulate the gut–brain axis, thereby promoting cognition and mental wellness. However, clinical research is essential to confirm these potential benefits. Full article

Metallo-phthalocyanines (MPcs) are versatile materials with applications in electroanalysis because of their superior catalytic properties. This review presents the electrochemical methods based on MPc-modified electrodes and reports some of their remarkable properties and applications in the electroanalysis of monoamine neurotransmitters and biomolecules that play a crucial role in vital functions of the human body. The development of electrocatalytic chemically modified electrodes is based on their ability to provide a selective and rapid response toward a specific analyte in complex media without the need for sample pretreatment. The explanation of several phenomena occurring at the MPc-modified electrode surface (e.g., MPc-mediated electrocatalysis), the advantages of promoting different electron transfer reactions, and the detection mechanism are also presented. The types of MPcs and different materials, such as carbon nanotubes and graphene, used as substrates for modified working electrodes are discussed. Modifying the properties of MPcs through various interactions, or combining MPcs with carbonaceous materials, creates a synergistic effect. Such hybrid materials present both extraordinary catalytic and increased conductivity properties. We conducted a compilation study based on recent works to demonstrate the efficacy of the developed sensors and methods in sensing monoamine neurotransmitters. We emphasize the analyte type, optimized experimental parameters, working range, limits of detection and quantification, and application to real samples. MPc–carbon hybrids have led to the development of sensors with superior sensitivity and improved selectivity, enabling the detection of analytes at lower concentrations. We highlight the main advantages and drawbacks of the discussed methods. This review summarizes recent progress in the development and application of metallo-phthalocyanine-modified electrodes in the electroanalysis of monoamine neurotransmitters. Some possible future trends are highlighted. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterised by the accumulation of neurotoxic substances in the brain, ultimately leading to progressive cognitive decline. The complex aetiology and involvement of multiple molecular targets in AD pathogenesis have made discovering effective therapeutic agents particularly challenging. Targeting multiple proteins simultaneously with a single therapeutic agent may offer a promising strategy to address the disease’s multifaceted nature. Methods: This study employed advanced computational methodologies to perform multitargeted molecular docking of FDA-approved drugs against four key AD-associated proteins implicated in disease progression. Among the screened compounds, Rebamipide—a drug conventionally used for treating gastrointestinal disorders—demonstrated notable binding affinities across all targets. Pharmacokinetic predictions, interaction fingerprinting, WaterMap analysis, density functional theory (DFT) calculations, and 100 ns MD simulations were performed for each protein–ligand complex to evaluate its multitarget potential. Results: Rebamipide bound effectively to the NR1 ligand-binding core, suggesting modulation of glutamatergic signalling while reducing β-secretase production and regulating neurotransmitter homeostasis through inhibiting monoamine oxidase-A. Furthermore, Rebamipide enhanced cholinergic neurotransmission by inhibiting human acetylcholinesterase, potentially improving cognitive function. Pharmacokinetic analyses confirmed favourable drug-like properties. Molecular interaction fingerprints revealed consistent hydrogen bonding, hydrophobic contacts, and π-π stacking interactions. WaterMap analysis indicated thermodynamically favourable water displacement upon binding, enhancing ligand affinity. DFT analysis of Rebamipide showed a 4.24 eV HOMO-LUMO gap, with ESP values ranging from −6.63 × 10⁻² to +6.63 × 10⁻² A.U., indicating reactive sites. TDDFT predicted strong UV absorption at 314 nm with a peak intensity of ~6500 L mol⁻¹ cm⁻¹. MD simulations over 100 ns demonstrated minimal structural deviations and stable ligand–protein complexes, reinforcing its multitarget efficacy. Conclusions: The comprehensive in silico investigation highlights Rebamipide as a promising multitargeted therapeutic candidate for Alzheimer’s disease. Its ability to modulate multiple pathogenic pathways simultaneously underscores its potential utility; however, these computational findings warrant further experimental validation to confirm its efficacy and therapeutic relevance in AD. Full article

As the number of cancer patients and survivors increases, we face a rising challenge: the long-term impact of the adverse effects of cancer treatment. One of the known adverse effects is chemotherapy-induced peripheral neuropathy (CIPN), which courses with pain complaints. The treatments of CIPN have reduced efficacy. The neurobiological causes of CIPN have been mainly ascribed to peripheral nerve damage, but recent studies show effects in the brain, namely in the descending pain modulatory systems. Physical exercise seems to be associated with better outcomes in CIPN patients, but the mechanisms underlying the effects have not been discussed, namely considering the recent results of the effects of CIPN in brain structures involved in pain modulation. In this critical review, we propose that the beneficial effects of exercise in CIPN also have central mechanisms, namely neuroinflammation and oxidative stress, as well as changes in the actions of neurotransmitters and neurotrophic factors, with a direct effect on optimizing the endogenous pain modulation, namely opioids, monoamines, and endocannabinoids. The effects are multifactorial, as mood improvement and the other psychological benefits of exercise should be considered. The emerging role of the microbiome, which is affected during CIPN, also needs to be considered. This review critically synthesizes the available literature to highlight how the neurobiological effects of physical exercise make it a promising strategy for managing CIPN, both from preventive and treatment perspectives. Full article

The neurotransmitter sodium symporters (NSSs) play critical roles in the neurotransmission of monoamine and amino acid neurotransmitters and are the molecular targets of therapeutic agents in the treatment of several psychiatric disorders. Despite significant progress in characterizing structures and transport mechanisms, the management of conformational transitions by structural elements coupled with ion and substrate binding remains to be fully understood. In the present study, we biochemically identified a conserved GX₉P motif in the fifth transmembrane domain (TM5) of the serotonin transporter (SERT) that plays a vital role in its transport function by facilitating conformational transitions. Mutations of the conserved Gly278 or Pro288 in the GX₉P motif dramatically decreased specific transport activity by reducing the substrate binding-induced conformational transitions from an outward-open to an inward-open conformation. In addition, cysteine accessibility measurements demonstrated that the unwinding of the intracellular part of TM5 occurs during conformational transitions from an outward-open state, through an occluded state, to an inward-open state and that substrate binding triggers TM5 unwinding. Furthermore, mutations of the GX₉P motif were shown to result in destructive effects on TM5 unwinding, suggesting that the GX₉P motif controls conformational transitions through TM5 unwinding. Taken together, the present study provides new insights into the structural elements controlling conformational transitions in NSS transporters. Full article

Serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are key monoamine neurotransmitters regulating behaviors, mood, and cognition. 5-HT affects early brain development, and its dysfunction induces brain vulnerability to stress, raising the risk of depression, anxiety, and autism in adulthood. These neurotransmitters are synthesized from tryptophan and tyrosine via hydroxylation and decarboxylation, and are metabolized by monoamine oxidase (MAO). This review aims to summarize the current findings on the role of dietary phytochemicals in modulating monoamine neurotransmitter biosynthesis, metabolism, and function, with an emphasis on their potential therapeutic applications in neuropsychiatric disorders. Phytochemicals exert antioxidant, neurotrophic, and neurohormonal activities, regulate gene expression, and induce epigenetic modifications. Phytoestrogens activate the estrogen receptors or estrogen-responsive elements of the promoter of target genes, enhance transcription of tryptophan hydroxylase and tyrosine hydroxylase, while inhibiting that of MAO. These compounds also influence the interaction between genetic and environmental factors, potentially reversing dysregulated neurotransmission and the brain architecture associated with neuropsychiatric conditions. Despite promising preclinical findings, clinical applications of phytochemicals remain challenging. Advances in nanotechnology and targeted delivery systems offer potential solutions to enhance clinical efficacy. This review discusses mechanisms, challenges, and strategies, underscoring the need for further research to advance phytochemical-based interventions for neuropsychiatric diseases. Full article

Monoamine neurotransmitters play a critical role in the development and function of the nervous system. In this study, we investigated the impact of parental serotonin (5-HT) modulation on the monoamine balance in the identified apical neurons of Lymnaea stagnalis embryos and its influence on embryonic locomotor activity. Using immunocytochemical and pharmacological approaches, we detected serotonin in the apical neurons of veliger-stage embryos, observing that the relative 5-HT level within these neurons varied with seasonal conditions. Pharmacological elevation of parental 5-HT levels significantly increased the relative 5-HT level in the oocytes and subsequently in the apical neurons of their offspring. Notably, while the relative dopamine (DA) levels in these neurons remained stable, the increase in the relative 5-HT level significantly enhanced the embryos’ rotational locomotion. The expression of tryptophan hydroxylase (TPH), a key enzyme in serotonin synthesis, is a prerequisite for the elevation of the relative 5-HT level in apical neurons and is detected as early as the gastrula stage. Importantly, neither a reduction of 5-HT in the maternal organism by chlorpromazine application nor its pharmacological elevation via serotonin precursor (5-HTP) application at the cleavage stage affected the monoamine balance in apical neurons. These findings provide novel insights into how the parental 5-HT level selectively alters the monoamine phenotype of the identified neurons, offering a model for studying environmentally induced neural plasticity in early development. Full article

Background: Depression is one of the most serious and common health problems among the youth population and is responsible for the initiation of many diseases. As per the World Health Organization, 3.8% of the population suffers from mental depression, globally. The monoamine oxidase-A (MAO-A) enzyme is responsible for the degradation of neurotransmitters leading to lower levels of neurotransmitters. Methods: Chalcones (C1-C15) were synthesized by reacting substituted acetophenone with various benzaldehydes in a basic ethanolic solvent at 80 °C under microwave irradiation conditions. To compare the reaction time and product yield, a conventional method of synthesis of chalcones was also performed. The synthesized chalcones (C1-C15) were spectroscopically characterized and screened initially for inhibitory activities against MAO-A and MAO-B. The best active compounds were undertaken for IC₅₀ determination against MAO-A enzyme followed by the reversibility of inhibition analysis and the antioxidant assay. Moreover, in silico molecular docking and ADME pharmacokinetic investigations were accomplished. Results: Most of the compounds inhibited MAO-A, specifically, compounds C14 and C6 exhibited the highest inhibition at IC₅₀ values of 7.91 ± 0.08 μM and 8.45 ± 0.19 μM, respectively. Both these compounds exhibited a reversible MAO-A inhibition displaying up to 60% recovery of enzymatic activity when diluted with substrate (Tyramine). The results of the in silico study indicated docking scores of −9.56 Kcal/mol (C14) and −9.45 Kcal/mol (C6) and exhibited a π-π stacking interaction with the crucial amino acid Trp-397. The compounds were determined to cross the blood–brain barrier (BBB) and displayed favorable gastrointestinal (GI) absorption. Further, the antioxidant assay results demonstrated that the synthesized compounds possess modest free radical scavenging potential. Conclusions: This study displayed the MAO-A inhibitory potential of morpholine-substituted chalcones as a promising pharmacophore for the development of novel antidepressant lead compounds. Full article

Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article