Search Results (272)

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

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

Food components and herbal substances can inhibit or enhance the therapeutic effects of drugs, thus influencing their efficacy and safety. As relatively little in known of these interactions, the aim of this review is to shed further light on the potentially dangerous influences that food and herbs may have on cytochrome P450 enzyme (CYP) and monoamine oxidase (MAO) activity in the first stage of drug biotransformation. The review includes documented cases in which such interactions have led to health complications in patients. For example, fruit juices, such as grapefruit juice, cranberry juice, and pomegranate juice, have been found to interact with drugs, and to particularly inhibit CYP450 activity, and commonly used herbs are known to inhibit (e.g., Astragalus membranous) or induce (e.g., Hypericum perforatum) CYP enzymes involved in drug metabolism. CYP is also induced by polycyclic aromatic hydrocarbons (PAHs), found in grilled meat and tobacco smoke. The paper also discusses the toxic effects of tyramine, present in inter alia blue cheese, resulting from interactions with MAO-metabolised drugs. Most importantly, while the quantity of food and herbs consumed plays a significant role in the described drug interactions, it is possible for toxic effects to be observed even after the consumption of relatively small amounts. Patients are encouraged to consult a healthcare provider about any potential drug interactions that may occur when starting a new medication. Full article

Background: Resveratrol has been shown to modulate stress-related anxiety by reducing brain monoamine oxidase A (MAO-A) activity. However, the molecular mechanism underlying this neurochemical effect remains unknown. In this study, we employed in silico approaches to investigate the binding affinity of resveratrol and its predominant blood metabolite, resveratrol glucuronide, to specific sites on MAO-A. Methods: For the in silico analysis, we employed molecular docking and molecular dynamics simulations. Within the liver–brain axis, we investigated the role of hepatic MAO-A in the development of anxiety. The activity of whole-brain MAO-A was compared with its activity in specific brain regions, including the amygdala, hippocampus, and prefrontal cortex. Results: Our findings suggest the presence of an allosteric site on the enzyme that accommodates these compounds. Furthermore, in vivo experiments demonstrated that high-dose resveratrol suppresses MAO activity not only in the brain but also in the liver of stress-exposed rats. The in vivo results are interpreted in the context of an allosteric site on MAO-A in both the brain and liver, which may mediate the interaction with resveratrol and its metabolite. Conclusions: The primary outcomes of the study include the identification of the role of hepatic MAO-A in the development of anxiety-like behavior, as well as the determination of resveratrol dose ranges at which it functions as an allosteric modulator of MAO-A activity. Full article

Culinary herbs and spices are valued worldwide for their flavor, aroma, and medicinal benefits. They encompass diverse bioactive metabolites, such as polyphenols and terpenoids, which contribute to plant defense and offer anticarcinogenic, anti-inflammatory, antioxidant, and cognitive-enhancing effects. This study aimed to establish the volatile fingerprint of culinary herbs (lemon verbena, chives, basil, sage, coriander, and parsley) and spices (curcuma, nutmeg, cumin, black pepper, Jamaica pepper, and juniper berry) using headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME/GC-MS). The predominant volatile organic metabolites (VOMs) identified were subjected to in silico molecular docking simulations of anti-Alzheimer’s (e.g., acetylcholinesterase (AChE), butyrylcholinesterase (BChE)), antioxidants (e.g., monoamine oxidase B (MAO-B), inducible nitric oxide synthase (iNOS)), and anti-inflammatory receptors (e.g., 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2)). The culinary herb and spice extracts were also subjected to in vitro assays to evaluate their potential as antioxidant (DPPH, ABTS, and ORAC) and anti-inflammatory (% protein denaturation) agents. A total of 121 VOMs were identified in the culinary herbs and spices, with the predominant chemical families being monoterpenoids (48.3%), sesquiterpenoids (14.0%), esters (11.9%), and carbonyl compounds (8.8%). In silico molecular docking simulations revealed that cuminaldehyde, β-caryophyllene, γ-curcumene, germacrene D, and τ-cadinol exhibited the strongest inhibitory activities against the selected receptors. Among the extracts, Jamaica pepper showed the highest antioxidant and anti-inflammatory activities, while lemon verbena exhibited the lowest ones. These findings highlight the promising potential of the studied culinary herbs and spices in the modulation of inflammatory processes related to Alzheimer’s disease. However, further investigations, particularly clinical studies, are recommended to validate these results and explore their therapeutic applications. Full article

Neurodegenerative diseases involve oxidative stress and enzyme dysregulation, necessitating novel neuroprotective agents. This study evaluates the neuroprotective and antioxidant potential of seven pyrrole-based compounds with predicted radical scavenging activity and inhibitory effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE). The compounds were tested in vitro using SH-SY5Y neuroblastoma cells and subcellular rat brain fractions, including synaptosomes, mitochondria, and microsomes. Neuroprotective and antioxidant effects were assessed in oxidative stress models, including H₂O₂-induced stress in SH-SY5Y cells, 6-hydroxydopamine toxicity in synaptosomes, tert-butyl hydroperoxide-induced stress in mitochondria, and non-enzyme lipid peroxidation in microsomes. In silico screening for lipophilicity, hydrogen bonding, total polar surface area (TPSA), and ionization properties, was performed to evaluate bioavailability. All compounds exhibited a weak neurotoxic effect on the subcellular fractions at a concentration of 100 µM. However, in oxidative stress models, they demonstrated significant neuroprotective and antioxidant effects at 100 µM. In SH-SY5Y cells, compounds 7, 9, 12, 14, and 15 exhibited low toxicity and strong protective effects at concentrations as low as 1 µM. In silico analysis prioritized compounds 1, 7, 9, 12, and 14 for further development based on their favorable bioavailability. The tested pyrrole-based compounds exhibit promising neuroprotective and antioxidant properties, with several candidates showing potential for further development based on both in vitro efficacy and predicted oral bioavailability. Full article

Coumarin represents a privileged structural motif that is quite common in nature-derived and synthetic bioactive molecules. Some of us have recently described the straightforward preparation of complex furo[3,2-c]coumarins through a sequential double coupling protocol. Aiming at finding novel chemical probes for the modulation of key anti-Alzheimer’s targets, a small subset of furo[3,2-c]coumarin prototypes and their non-aromatic synthetic precursors were tested in vitro as inhibitors of ChEs (acetyl- and butyrylcholinesterase, AChE and BChE) and MAOs (monoamine oxidases A and B, MAO A and MAO B). All compounds were low-micromolar AChE inhibitors devoid of toxic effects against SH-SY5Y cells. Lineweaver-Burk plots and docking simulations suggested mixed-type kinetics for inhibitor 3d (IC₅₀ = 4.1 μM toward AChE). Its promising inhibitory profile encompasses additional, highly selective, activity against monoamine oxidase B, with a submicromolar IC₅₀ value (561 nM). Full article

Serotonin 5HT_1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using the selective 5HT_1A receptor positron emission tomography (PET) imaging agent, [¹⁸F]mefway, autoradiographic studies from postmortem human brains of AD, PD, and cognitively normal (CN) subjects were carried out. Levels of [¹⁸F]mefway binding were compared with monoamine oxidase A (MAO-A) measured using [¹⁸F]FAZIN3 binding and dopamine D2/D3 receptors measured using [¹⁸F]fallypride binding in the same subjects. Autoradiograms of brain sections of the anterior cingulate and corpus callosum from CN, PD, and AD subjects (n = 6 in each group) were analyzed. Significant increased binding of [¹⁸F]mefway was found in the AD (+30%) and PD (+11%) brains compared to CN brains. This increase positively correlated to increased [¹⁸F]FAZIN3 binding, suggesting greater 5HT_1A receptor availability when MAO-A levels are higher. Differences in [¹⁸F]fallypride binding in the three groups were not significant. Our results support the finding that the availability of 5HT_1A receptors in AD and PD is elevated in the anterior cingulate cortex and is negatively correlated with MAO-A. This upregulation may potentially be a response to lower serotonin levels due to the increased levels of MAO-A activity in this brain region or other neuroinflammatory changes. Thus, 5HT_1A receptors may be a potential target for diagnostic and therapeutic approaches for AD and PD. Full article

There is an urgent need to identify interventions that broadly target aging-related cognitive decline and progression to Alzheimer’s disease (AD). Bottlenose dolphins (Tursiops truncatus) have histologic changes similar to AD in humans, and they also develop shared age-associated co-morbidities identified as risk factors for AD in humans, including type 2 diabetes, ferroptosis, and iron overload, which can be driven by nutritional C15:0 deficiency. We hypothesized that (1) dolphins would have amyloid beta (Aβ) plaques and neuroinflammation that paralleled that of humans in relation to age-related progression, quantitative concentration, and brain region; and (2) C15:0 would have dose-dependent activities relevant to protecting cognitive health. Quantitative immunohistochemistry staining was used to assess 68 tissues from archived brains of 19 Navy dolphins to evaluate associations among amyloid beta (Aβ) plaques and neuroinflammation by brain region, sex, and age group. Further, dose-dependent C15:0 activities, using a third-party panel intended to screen for potential AD therapeutics, were evaluated. Similar to humans, dolphins had the highest Aβ plaque density variation in the hippocampus (90th percentile of 4.95 plaques/mm²), where plaque density increased with age (p = 0.05). All measured markers of neuroinflammation were detected, including the highest concentrations of activated microglia (CD68⁺) in the hippocampus (0.46 ± 0.38 cells/mm²). C15:0 was a dose-dependent inhibitor of two targets, fatty acid amide hydrolase (FAAH) (IC₅₀ 2.5 µM, 89% maximum inhibition at 50 µM relative to URB597) and monoamine oxidase B (MAO-B) (IC₅₀ 19.4 µM, 70% maximum inhibition at 50 µM relative to R(-)-Deprenyl). These activities have demonstrated efficacy against Aβ formation and neuroinflammation, including protection of cognitive function in the hippocampus. These findings suggest that, in addition to protecting against AD co-morbidities, C15:0 may play a distinct role in supporting cognitive health, especially at higher concentrations. Full article

Background: Psilocybin has shown promise in therapeutic applications for mental disorders. Understanding the pharmacokinetics of psilocybin and its active metabolite psilocin is crucial for optimizing its clinical use and minimizing adverse effects. Methods: This systematic review involved a comprehensive search across MEDLINE, APA PsycINFO, and Embase databases, from inception to December 2024, identifying original studies that investigated the pharmacokinetics of psilocybin. Results: Fourteen studies met the inclusion criteria: eight laboratory-based and six clinical studies. Laboratory studies used animal models or in vitro systems, while clinical studies included 112 healthy human participants. Psilocybin is rapidly dephosphorylated to psilocin, which is absorbed with Tmax values ranging from 1.8 to 4 h following oral administration. Cmax varied dose-dependently, from 8.2 ± 2.8 ng/mL (plasma) to 871 ng/mL (urine). One study reported psilocin bioavailability at 52.7 ± 20%. The volume of distribution was extensive, ranging from 277 ± 92 L to 1016 L, suggesting significant tissue distribution. Psilocin metabolism is primarily mediated by CYP2D6 and CYP3A4, with secondary contributions from monoamine oxidase A. It undergoes further hepatic biotransformation into 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol. Elimination half-life varied across studies, ranging from 1.5 to 4 h. Conclusions: Psilocybin pharmacokinetics demonstrate significant variability based on dosage, route, and species. CYP enzymes play a critical role in its metabolism, highlighting the potential for drug–drug interactions. These findings underscore the importance of further research to elucidate psilocybin’s pharmacokinetic profile, which is assessed in vivo by its active metabolite psilocin. Full article

Hawm Gra Dang Ngah rice (HDNR) is a red rice variety cultivated in Thailand’s southern border region, yet its biological properties have not been extensively studied. This study investigates the effects of HDNR extracts on bioactive constituents, spectral fingerprints, and antioxidant capacities. We evaluated the inhibitory effects of aqueous (HDNR-W) and ethanolic (HDNR-E) extracts on monoamine oxidase (MAO), α-glucosidase, and HMG-CoA reductase activities, as well as their cytotoxicity in normal and cancer cells. The results demonstrated that HDNR-E contained significantly higher concentrations of phenolic compounds, flavonoids, and anthocyanins compared to HDNR-W. In contrast, HDNR-W exhibited greater amino acid content than HDNR-E. FT-IR analysis revealed solvent-specific interactions that influenced compound solubility, highlighting distinct extraction efficiencies. Antioxidant assays showed HDNR-E to be markedly more potent, with superior performance in DPPH, ABTS, metal chelation, and FRAP assays, as evidenced by its lower IC₅₀ values relative to HDNR-W. Furthermore, HDNR-E displayed significantly stronger inhibitory activity against both MAO and α-glucosidase compared to HDNR-W. Conversely, HDNR-W demonstrated greater inhibitory efficacy toward HMG-CoA reductase than HDNR-E. Furthermore, HDNR-E exhibited significant antiproliferative effects against A549 lung cancer and MCF-7 breast cancer cells without affecting normal cells. These results highlight the potential of HDNR-E as a valuable source of bioactive compounds and underscore the importance of solvent selection in enhancing the health benefits of rice extracts. 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

Plant-based products are widely used in the food industry. This study aims to develop neurofunctional ingredients derived from mung beans with mulberry fruit powder, evaluate their phytochemical contents (total phenolic, anthocyanin, and GABA contents), impact of anti-oxidant activities (DPPH free radical scavenging inhibition and Ferric Reducing Ability Power (FRAP)) and neuroprotective activities (acetylcholinesterase (AChE), monoamine oxidase (MAO), MAO type A, and gamma-aminobutyric acid transaminase (GABA-T)), and focus on their shelf life. Result: A total of nine ratios of mung beans and mulberry fruit powder mix were evaluated, which showed that a ratio of 1:3 (g/g) provided better IC50 values of antioxidant and neuroprotective activities than other ratios, and showed a combination index (CI < 1) which was interpreted as a synergistic effect on AChE inhibition. Thus, this ratio was selected to make freeze-dried powder (mung bean mix mulberry fruit powder (MMP)), and its shelf life was evaluated as showing stability in its phytochemical contents (except GABA, which was reduced by more than 50% at 30 ± 2 °C) and antioxidant and neuroprotective activities, which remained stabilized at more than 50% in both real-time and accelerated conditions for 6 months and 8 weeks, respectively. During 1 to 6 months of storage at 4 °C, IC50 values of FRAP showed inhibited DPPH, AChE, MAO, MAO-A, and GABA-T levels in ranges of 4.43–6.69 mg/mL, 4.10–4.68 mg/mL, 5.18–5.90 mg/mL, 4.95–5.43 mg/mL, 5.93–6.42 mg/mL, and 5.05–5.53 mg/mL respectively, not significantly different when compared to 0 months. Conclusion: These findings indicate that the shelf life of the bioactivities of MMP remain stabilized for up to six months, so it could be applied in the food industry for use as a healthy plant-based supplement. Full article

Recent studies have demonstrated that circuit activation in vivo can regulate proliferation of lateral ventricular neural stem cells (LV NSCs), although the underlying molecular and cellular mechanisms are not yet fully understood. Here, we investigated the role of GABAergic signaling in the interaction between LV NSCs and the anterior cingulate cortex-subependymal-choline acetyltransferase⁺ (ChAT⁺) neuron (ACC-subep-ChAT⁺) circuit. We found that monoamine oxidase B (MAOB), a key enzyme involved in gamma-aminobutyric acid (GABA) synthesis, is expressed in LV NSCs, and that activation of the ACC-subep-ChAT⁺ circuit can modulate MAOB activity. Additionally, LV NSCs express LRRC8D, a core component of volume-regulated anion channels, and GABA transporter-1 (GAT-1, SLC6A1). We show evidence that, through GABA signaling, LRRC8D and GAT-1 can provide a negative feedback signal to ChAT⁺ neurons, a key component of the ACC-subep-ChAT⁺ circuit that regulate proliferation of LV NSCs. These findings suggest that MAOB-driven GABA synthesis, LRRC8D-regulated chloride and GABA transport, and GAT-1-facilitated GABA reuptake can regulate neural circuit activation and influence NSC proliferation dynamics in the LV. Full article

Background: Monoamine oxidase A (MAOA) has a role in metabolising different biogenic amines, including dopamine. Functional studies have revealed the effect of promoter region variants on the transcriptional activity of the MAOA that consequently affects the homeostasis of the biogenic amines which might implicate in the aetiology of multiple psychiatric conditions. Objectives: The current study aimed to determine the influence of the promoter region 30 base pair (bp), a variable number of tandem repeats (VNTR) of the MAOA, on its serum levels and association with schizophrenia (SHZ), bipolar disorder (BD), and major depressive disorder (MDD) in the Pakistani population. Methods: A total of 1062 subjects [MDD n = 416, BD n = 200, SHZ n = 97 and controls n = 349], were genotyped for MAOA-30bp µVNTR through standard polymerase chain reaction technique and logistic regression was applied to determine the genetic association. Serum MAOA levels were determined through enzyme-linked immunosorbent assay (ELISA) and the Mann-Whitney U test was applied. Results: In genotype analysis, eight different repeat (R) alleles of MAOA-30 bp µVNTR were observed, where 4.5R, 5.5R, and 6R were the rare repeats found in the current Pakistani cohort. In serum-based analysis the total MAOA serum levels were found to be significantly elevated in SHZ; however, in sub-group analysis, significantly higher serum levels of MAOA were observed only in the rare allele groups of MDD, BD, and SHZ. Conclusions: The current study gives us further insights into the complex nature of MAOA regulation and its genetic and serum-levels association with different psychiatric conditions. Full article