Search Results (821)

Background/Objectives: Citrus limon leaf essential oil (EO) is traditionally used for its calming and cognitive-enhancing properties. Although the chemical composition of C. limon leaf essential oils (EOs) obtained by means of hydrodistillation (HD) and solvent-free microwave extraction (SFME) has been previously characterized, the influence of the extraction method on their neuroprotective efficacy and dose–response effects remains insufficiently explored. In the present study, EOs obtained by means of HD (CEH) and SFME (CEM) were compared for their behavioral, biochemical, and in silico neuroprotective effects against scopolamine (SCOP)-induced cognitive and anxiety-like impairments in adult zebrafish. Methods: Adult Tübingen zebrafish were exposed to CEH or CEM via immersion at 10, 100, and 150 µL/L for 19 days prior to SCOP challenge (100 µM). Cognitive performance was evaluated using the Y-maze and novel object recognition (NOR) tests, while anxiety-like behavior was assessed using the novel tank test (NTT) and novel approach test (NAT). Brain acetylcholinesterase (AChE) activity and oxidative stress markers were quantified. Molecular docking analyses were conducted to investigate interactions between major EO constituents and AChE and monoamine oxidase A (MAO A). Results: Both CEH and CEM significantly attenuated SCOP-induced memory deficits, improved spontaneous alternation and NOR discrimination, and reduced anxiety-like behaviors. These effects were associated with AChE inhibition and restoration of redox balance. Notably, CEM generally exhibited stronger neurobehavioral and biochemical effects at comparable doses. In silico analyses supported these findings, revealing favorable binding affinities of key EO constituents toward cholinergic and monoaminergic targets. Conclusions: This study demonstrates that the extraction method influences the neuroprotective efficacy of C. limon leaf EOs. While both CEH and CEM exert antioxidant and cholinergic modulatory effects, CEM shows enhanced neuroprotective potential in a zebrafish model of SCOP-induced cognitive impairment, supporting the relevance of extraction-dependent biological profiling in EO-based neurotherapeutic research. Full article

Neurodegenerative disorders (NDs), such as Alzheimer’s disease and Parkinson’s disease (PD), represent a significant challenge for ageing populations, with their prevalence increasing worldwide. Elevated human Monoamine Oxidase B (hMAO-B) activity has been related to neurodegenerative progression, where it contributes, among others, to oxidative stress and neuroinflammation. The identification and optimization of selective hMAO-B inhibitors is therefore pivotal in addressing the progression of NDs. In this work we introduced 2-aroylbenzothiophene analogues as promising agents to mitigate neurodegeneration. The synthesized compounds were screened against hMAO-A and hMAO-B, identifying compounds 4, 11, and 12 as the most promising. In vitro studies in hGF and SH-SY5Y cells revealed distinct toxicity profiles, with compound 4 being the least tolerated at 100 µM. ROS generation was investigated as a possible mechanism underlying this toxicity. Compounds 4 (12.5 µM), 11, and 12 (100 µM) were further evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity in SH-SY5Y cells, showing a modest neuroprotective effect after 72 h at a sub-toxic 6-OHDA concentration (250 µM), comparable to the clinically used hMAO-B inhibitor (R)-(−)-Deprenyl at 100 µM. Finally, molecular modelling studies revealed that compound 4 establishes key stabilizing interactions within hMAO-B, accounting for its high inhibitory potency and selectivity over hMAO-A. Full article

The pathogenesis of Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic signaling, resulting in motor dysfunction. Although monoamine oxidase (MAO) inhibitors are clinically used in PD, their long-term efficacy and safety remain limited. In the present study, three novel N-benzylpyrrolidine derivatives (3e, 3f, and 3i), previously identified as dual MAO-A/B inhibitors in silico and in vitro, were pharmacologically evaluated in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The compounds were administered intraperitoneally starting 2 days prior to MPTP exposure and continuing for 6 days thereafter. Repeated administration of the compounds did not alter striatal dopamine (DA) levels under basal conditions, indicating no detectable modulation of dopaminergic tone in vivo. All three derivatives ameliorated MPTP-induced motor deficits. Compounds 3f and 3i improved motor function without detectable changes in striatal DA levels, whereas compound 3e partially restored striatal DA levels, similar to the positive control. In addition, compound-specific alterations in hippocampal pro-inflammatory cytokines were observed, including increased levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) following 3e administration. Together, these findings provide in vivo pharmacological characterization of novel MAO-targeting derivatives and reveal differential behavioral, neurochemical, and cytokine profiles among the tested compounds, supporting further mechanistic investigation. Full article

In recent years, psychopharmacology has experienced a significant challenge, highlighting a renewed and strong scientific interest in psychedelics as breakthrough therapies for mental disorders. Psychedelics can influence cognitive and emotional processes, showing solid therapeutic potential, particularly in treatment-resistant psychiatric disorders. Amongst the most promising compounds, ayahuasca and its main psychoactive component, N,N-dimethyltryptamine (DMT), have received considerable attention. Ayahuasca is a psychoactive brew traditionally prepared from the liana Banisteriopsis caapi and the leaves of Psychotria viridis. Its psychoactive properties derive mainly from DMT, while β-carbolines, which act as monoamine oxidase-A (MAO-A) inhibitors, prevent the metabolic degradation of DMT, enhancing its bioavailability and allowing oral administration. In contrast, in monotherapy, DMT or its analog 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is generally administered via alternative routes, like inhalation, intranasal, or intravenous delivery. DMT is primarily a serotonin (5-HT)2A receptor partial agonist, whereas 5-MeO-DMT has a higher affinity for the 5-HT1A receptor compared to 5-HT2A, though other receptor targets are engaged, fostering neuroplasticity and a reorganization of brain networks involved in perception, cognition, and mood regulation. Despite limited clinical trials, current evidence offers an optimistic outlook on DMT and 5-MeO-DMT efficacy for treatment-resistant depression (TRD) and major depressive disorder (MDD), whereas evidence for other mental disorders studies is still preliminary. There are four phase II studies with 5-MeO-DMT and one with DMT for TRD, while there are two phase II studies with DMT fumarate for MDD. Beyond their therapeutic potential, psychedelics also represent powerful tools for exploring the human mind, offering valuable insights into brain function and mental health. Full article

Differentiated human neuroblastoma (SH-SY5Y) cells were exposed to either 0.2 μM nicotine, a tobacco smoke preparation (TPM) diluted to the same nicotine concentration, or a cocktail of seven tobacco smoke monoamine oxidase inhibitors (MAOIs) at the concentrations measured in the TPM. Treatment occurred for 3 days, such that the cellular monoamine oxidase (MAO) concentration was reduced by approximately 50% in both the TPM and MAOI cocktail exposure groups. Changes in MAO gene expression after exposure to the different treatments were determined using qPCR, and the effect of these exposure treatments on global gene expression was also examined using mRNA sequencing. No change in MAOA and MAOB gene expression levels was observed, after any treatment, either using qPCR or mRNA sequencing. The MAOI versus control treatment comparison revealed that four genes were >2-fold down-regulated (ZNF727, RP11-310E22.4, CRYM, SEMA3F), and 19 genes were up-regulated after 3 days’ exposure to the MAOI cocktail. Many of these differentially expressed genes were linked with disease conditions related to smoking and addiction. Exposure to nicotine and TPM each resulted in up- and down-regulation of different sets of genes. The results indicate that changes in MAO gene expression are unlikely to be responsible for the changes in MAO activity. The association between genes whose expression changes with tobacco MAO treatment and smoking-related diseases and addiction suggests the central role that MAO inhibition may play in mediating the effects of smoking on smokers. Full article

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous system, the enteric nervous system, the prefrontal–cortico-pontine network, and the amygdala. Hypoxia–ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This “amplification” mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson’s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the “critical point” of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and/or immune biomarkers. Full article

Gastric cancer remains a leading cause of cancer-related mortality worldwide. Citrus fruits are rich in polyphenols, exerting antioxidant and chemo-preventive activities, and lemon peel represents a valuable source of such bioactive compounds. Previous studies showed that Citrus limon peel extracts (LPE) inhibited the activity of some enzymes of the antioxidant system and reduced the interleukin-6-dependent invasiveness of gastric and colon cancer cells. In the present study, we have investigated the effects of LPE on the human gastric adenocarcinoma AGS and MKN-28 cells and on the activity of a crucial redox enzyme, catalase (CAT). Indeed, LPE significantly reduced the cell viability and clonogenic potential of the gastric cancer cells and induced morphological changes indicative of cytotoxicity. Moreover, LPE modulated the intracellular redox homeostasis by decreasing levels of the hydrogen peroxide-related reactive oxygen species (ROS) while increasing those of superoxide anions and decreasing levels of superoxide dismutases (SODs). Western blotting analysis revealed that LPE downregulated CAT, SOD-1, SOD-2, and monoamine oxidase A (MAO-A) protein expression level in both cell lines. Finally, the extract inhibited CAT activity in a dose-dependent manner (IC₅₀ = 0.008 ± 0.003 mg/mL; K_i = 0.012 ± 0.002 mg/mL). These findings indicate that LPE exerts cytotoxic and redox-modulating effects through the inhibition of antioxidant enzymes and the alteration of ROS balance. Therefore, the agro-industrial by-product LPE could be considered as a promising natural source of polyphenolic compounds with potential applications in the prevention and therapy of gastric cancer. Full article

Chalcone-based derivatives were designed as dual-acting ligands targeting the histamine H₃ receptor (H₃R) and monoamine oxidase B (MAO-B), based on the lead compound DL76. Three series of compounds (1–18) were synthesised and characterised, including simple chalcones (1–9) and piperidinyl chalcones (10–18). All piperidinyl derivatives exhibited nanomolar affinity for human H₃R (hH₃R), with compounds 10–12 achieving K_i values ≤ 30 nM. Simple chalcones showed potent human MAO-B (hMAO-B) inhibition (IC₅₀: 0.85–337 nM), especially 3,4-dichloro derivatives. Compound 15 was the most active hybrid, with a K_i of 46.8 nM for hH₃R and an IC₅₀ of 212.5 nM for hMAO-B. Molecular docking and 250 ns simulations revealed stabilising interactions at both binding sites and clarified structural features behind dual activity. Preliminary ADMET profiling showed low Caco-2 permeability and rapid microsomal metabolism, mainly via hydroxylation. Compound 15 exhibited micromolar cytotoxicity in SH-SY5Y and HepG2 cells, induced G2/M arrest, disrupted mitochondrial homeostasis, and was genotoxic in Peripheral Blood Mononuclear Cells (PBMCs). Additionally, for H₃R ligands (15, DL76, pitolisant), the study reports the first use of Surface Plasmon Resonance Microscopy (SPRM) to assess their interactions with this receptor. Therefore, piperidinyl chalcones show promise as ligands with dual action on H₃R and MAO-B, useful in the treatment of neurodegeneration and/or CNS cancers. Full article

Oxidative stress plays a central role in the pathogenesis of neurodegenerative disorders, including Parkinson’s disease. Therefore, compounds with antioxidant and neuroprotective properties represent promising candidates for therapeutic development. N-pyrrolyl hydrazide-hydrazones, a class of pyrrole-based derivatives, have shown promising potential due to their diverse biological activities, including monoamine oxidase-B (MAO-B) inhibition. This study investigated the neuroprotective properties of 10 N-pyrrolyl hydrazide-hydrazones using experimental in vitro and in vivo models of neurodegeneration. The compounds were tested on SH-SY5Y neuroblastoma cells subjected to oxidative stress induced by 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP⁺). A battery of in vitro and in vivo experimental methods was used, including cell viability assay, reactive oxygen species (ROS) production, and apoptosis evaluation by quantifying the sub-G0/G1 cell population. In vivo neuroprotective efficacy was further tested in a rotenone-induced Parkinsonism mouse model by analyzing oxidative biomarkers and brain histopathology. Compounds 2, 4, 5, 6, and 10 significantly preserved cell viability in the 6-OHDA-induced toxicity model, while no protection was observed in the MPP⁺ model. Particularly compound 2 reduced ROS levels and apoptosis in SH-SY5Y cells. In vivo, compound 2 demonstrated strong antioxidant activity by maintaining glutathione levels and reducing lipid peroxidation. Histological analysis confirmed its protective effect against rotenone-induced neuronal damage. These results suggest that N-pyrrolyl hydrazide-hydrazones, especially compound 2, possess significant antioxidant and MAO-B inhibitory properties, supporting their potential as neuroprotective agents. Full article

Depression is a common, debilitating, and potentially life-threatening mental disorder affecting individuals across all age groups and populations. It represents one of the major challenges of contemporary medicine. It is estimated that more than 300 million people worldwide are affected, and patients with major depressive disorder (MDD) exhibit a significantly increased risk of suicide, underscoring the urgent need for effective and long-lasting therapeutic strategies. Growing evidence indicates that the pathophysiology of depression involves a complex interplay of genetic vulnerability, chronic stress, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity, collectively contributing to symptom heterogeneity and treatment resistance. In this review, we synthesize data derived from PubMed, Google Scholar, and ClinicalTrials.gov databases concerning pharmacological and non-pharmacological treatment strategies, with particular emphasis on their cellular and molecular mechanisms of action. We present currently used classes of antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), discussing their limitations in the context of contemporary pathophysiological models of depression. We then focus on emerging therapies targeting the glutamatergic, GABAergic, and dopaminergic systems, including ketamine, esketamine, (R)-ketamine, the dextromethorphan–bupropion combination (DMX–BUP), neurosteroids (zuranolone, brexanolone), as well as selective serotonin receptor modulators (gepirone ER) and dopaminergic modulators (cariprazine). The review is complemented by a discussion of non-pharmacological neuromodulatory approaches, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and photobiomodulation. Rather than providing another summary of clinical response indicators, this article integrates the molecular underpinnings of novel antidepressant agents and neuromodulation techniques with current concepts of depression pathophysiology, highlighting their relevance for the development of precise, mechanistically targeted, and multimodal treatment strategies. Full article

Background/Objectives: Many studies in the literature are increasingly focusing on how genes influence the development of individual behaviors and personality traits through genome sequencing. Most research indicates that complex behaviors and their characteristics are influenced by multiple genes, highlighting the crucial role of genetic studies in this field. Behavioral genetics, as a scientific discipline, investigates how genetic factors shape individuals’ behaviors and personality traits. The concepts of violence and aggression, observable in various contexts, have been extensively studied, with a particular focus on the underlying causes of these behaviors. In sports, where physical strength plays a significant role, regulations designed to prevent violent behaviors and aggressive attitudes contribute to the establishment of appropriate behavior patterns and discipline. Methods: This study aims to identify correlations between polymorphisms found in athletes and their responses to questionnaires, focusing on candidate genes known to influence personality and behavior traits, such as catechol-O-methyltransferase (COMT), serotonin transporter (5-HTT), monoamine oxidase (MAO-A), and serotonin 1A transporter (5-HT1A). A total of twenty licensed athletes participated in the study. Participants completed three standardized instruments: the Sportsmanship Behavior Scale (27 items), the Sports Emotion Scale (22 items), and the Anger-Control Scale (34 items). Following the acquisition of informed consent, buccal swab samples were collected for single nucleotide polymorphism (SNP) analysis targeting the COMT, MAO-A, 5- HT1A, and 5-HTT genes. Subsequent to sample collection and questionnaire administration, statistical analyses were conducted to evaluate the relationships among behavioral measures and genetic variants. Results: Overall, the findings point to gene-specific patterns in 5-HTT, MAO-A, and COMT, while no clear pattern emerged for 5-HT1A. Conclusions: Ultimately, this study provides an early exploration of aggression-related genetic patterns within the context of forensic sciences, highlighting preliminary trends and potential associations that may inform the design of future research. Full article

Major depressive disorder (MDD) was long framed as a single clinical entity arising from a linear stress–monoamine–hypothalamic–pituitary–adrenal (HPA) axis cascade. This view was shaped by forced swim and learned helplessness tests in animals and by short-term symptom-based trials using scales such as the Hamilton Depression Rating Scale (HAM-D) and the Montgomery–Åsberg Depression Rating Scale (MADRS). This “unitary cascade” view has been dismantled by advances in neuroimaging, immune–metabolic profiling, sleep phenotyping, and plasticity markers, which reveal divergent circuit-level, inflammatory, and chronobiological patterns across anxiety-linked, pain-burdened, and cognitively weighted depressive presentations, all characterized by high rates of non-response and relapse. Translationally, face-valid rodent assays that equated immobility with despair have yielded limited bedside benefit, whereas cross-species bridges—electroencephalography (EEG) motifs, rapid eye movement (REM) architecture, effort-based reward tasks, and inflammatory/metabolic panels—are beginning to provide mechanistically grounded, clinically actionable readouts. In current practice, depression care is shifting toward systems psychiatry: inflammation-high and metabolic-high archetypes, anhedonia- and circadian-dominant subgroups, formal treatment-resistant depression (TRD) staging, connectivity-guided neuromodulation, esketamine, selected pharmacogenomic panels, and early digital phenotyping, as endpoints broaden to functioning and durability. A central gap is that heterogeneity is acknowledged but rarely built into trial design or implementation. This perspective advances a plasticity-centered systems psychiatry in which a testable prediction is that manipulating defined prefrontal–striatal and prefrontal–limbic circuits in sex-balanced, chronic-stress models will reproduce human network-defined biotypes and treatment response, and proposes hybrid effectiveness–implementation platforms that embed immune–metabolic and sleep panels, circuit-sensitive tasks, and digital monitoring under a shared, preregistered data standard. Full article

Background: Glioblastoma is the most common and malignant primary brain tumor in adults, with current treatment presenting limited effectiveness. Therapeutic resistance stems largely from its marked molecular and cellular heterogeneity. Multitarget small molecules (MSMs) have emerged as a promising strategy for treating complex diseases such as cancer. In the present work, we generated a novel family of indole-based MSMs engineered to inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs) while simultaneously acting as histamine H₃ receptor (H3R) antagonists and sigma-1 receptor (S1R) agonists. Methods: To accomplish this, we combined selected pharmacophoric moieties from the parent compounds Contilisant and the HDAC pan-inhibitor Belinostat. Nine MSMs were synthesized. Results: Most of them showed cytotoxic activity in glioma cells. Among them, three molecules (MTP142, MTP156 and MTP150) were prioritized based on potency; these compounds impaired glioma stem cell (GSC) activity and were predicted to cross the blood–brain barrier. In vivo and multi-omic analyses centered on MTP150 showed significant tumor growth inhibition, both as monotherapy and in combination with temozolomide (TMZ). Transcriptomic and proteomic profiling of patient-derived GSCs revealed MTP150-induced disruption of cell cycle regulation pathways. Conclusions: Our data reveal the efficacy of a novel family of MSMs in the pre-clinical setting of glioblastoma. Full article

Background: Alzheimer’s disease and Parkinson’s disease are multifactorial disorders causing severe disability, rising with the increase in life expectancy. Currently, the identification of natural compounds useful against these disorders is becoming an urgent necessity. In this study, we used polyphenol-enriched extracts obtained from leaves of Mediterranean plants, which are important in animal feeding (Lotus ornithopodioides, Hedysarum coronarium, Medicago sativa) and in the human Mediterranean diet (Cichorium intybus). Objectives: The aims of this study were as follows: (i) tentative identification of the organic compounds present in the extracts; (ii) determination of their effect on the activity of monoamine oxidase (MAO)-A and MAO-B, key enzymes involved in the metabolism of aminergic neurotransmitters, as well as on protein expression level of these enzymes in cell lines expressing basal MAO-A and MAO-B. Methods: The ability of plant polyphenol extracts to inhibit MAO-A and MAO-B activity was assessed by in vitro enzyme assays. The protein expression level was analyzed by Western blotting. Results: Our data demonstrate that all the extracts behaved as MAO-A and MAO-B inhibitors, although to a different extent and enzyme inhibition mechanism; among them, the extract from L. ornithopodioides induced a decrease in MAO-A protein level in human AGS gastric adenocarcinoma and SH-SY5Y neuroblastoma cell lines. Conclusions: These data reinforce the hypothesis that a plant-based diet and/or integrative supplementation of pharmacological treatments can be considered for preventing and relieving symptoms of neurodegenerative diseases. Full article

Depression is a multifactorial disorder shaped by genetic, psychosocial, and biological influences, with hypotheses ranging from monoamine deficiency and neuroplasticity deficits to inflammation and stress-induced dysregulation. St. John’s wort (Hypericum perforatum L.) has long been used as an herbal antidepressant and is supported by clinical evidence for efficacy and safety in mild-to-moderate depression. While its multimodal mechanisms have been linked to neurotransmitter reuptake inhibition, neuroendocrine regulation, and modulation of neuroplasticity, recent findings suggest an additional role at the membrane level. Emerging lipidomic studies highlight that Ze 117, a low-hyperforin H. perforatum extract, counteracts stress- and glucocorticoid-induced increases in membrane fluidity by modulating lipid composition and cholesterol metabolism. These effects normalize receptor mobility and signal transduction, particularly of β1-adrenoceptors, and modulate glycerophospholipid metabolism in both cellular and animal models. Such membrane-stabilizing properties may represent a novel mechanistic pathway complementing classical neurochemical actions. This review revisits the mechanisms of St. John’s wort with a special focus on its impact on membrane lipids, positioning lipidomics as a promising tool for elucidating antidepressant activity. These insights may open avenues toward personalized therapeutic strategies in depression. Full article