Search Results (254)

Chronic depression is associated with oxidative stress, neuroinflammation, neurotransmitter imbalance, and Alzheimer’s-like changes. Current monoamine oxidase inhibitors have limited cognitive benefits and disease-modifying properties. A new nanotherapeutic, combining chitosan nanoparticles, propargylamino-1-(4-methylthiophenyl) propane (PAMTP), and L-tyrosine (En@PAMTP_Tyr), was developed. En@PAMTP_Tyr nanoparticles were ~140 nm in diameter, with a zeta potential of +27 mV and entrapment efficiencies of 73.45% for PAMTP and 90.85% for L-tyrosine. Drug release was pH-sensitive, favoring acidity. Intraperitoneal administration of En@PAMTP_Tyr reduced anhedonia, despair, cognitive deficits, and neuromuscular weakness, with efficacy matching or exceeding that of selegiline. In treated rats’ hippocampal tissue, En@PAMTP_Tyr increased superoxide dismutase and glutathione, normalized MAO and acetylcholinesterase activities, and corrected CUSD-induced TNF-α and IL-10 changes, showing antioxidant and anti-inflammatory effects. Histological analyses revealed that En@PAMTP_Tyr preserved CA1 pyramidal neurons, reduced β-amyloid levels, restored tau protein, and improved brain-derived neurotrophic factor levels, indicating reduced neurodegeneration. Molecular docking studies showed that PAMTP had high affinity for monoamine oxidase and acetylcholinesterase, supporting its role as an MAO-B inhibitor and cholinergic modulator. These findings suggest that En@PAMTP_Tyr is a promising nanoplatform for targeting MAO-B in depression, addressing mood, cognitive function, oxidative stress, inflammation, and Alzheimer-like pathology in the hippocampus. Full article

Background/Objectives: Methylxanthines, such as caffeine, exhibit neuroprotective properties in neurodegenerative conditions, partly linked to modulation of monoamine oxidase B (MAO-B) and oxidative stress pathways. This work aimed to design, synthesize and functionally characterize new caffeine-8-methylthioglycolic acid derivatives as selective MAO-B inhibitors with neuroprotective potential. Methods: A QSAR model was built on 94 studies of xanthine derivatives to guide the design of ten new semi- and thiosemicarbazides (Jas1–Jas10), followed by molecular docking to human MAO-B (PDB: 2V5Z) using Glide, GOLD and MM-GBSA binding free energy calculations. The target compounds were synthesized in relatively high yields, structurally confirmed by spectroscopic methods and tested in vitro for hMAO-A/B inhibition, as well as for neurotoxicity and neuroprotection in isolated mouse brain synaptosomes, mitochondria and microsomes under 6-hydroxydopamine (6-OHDA), tert-butyl hydroperoxide (t-BuOOH) and Fe/ascorbate (Fe²⁺/AA)-induced oxidative stress. Results: Docking and MM-GBSA identified Jas6 and Jas7 as the most stable MAO-B binders, with binding free energies approaching those of safinamide. All derivatives inhibited hMAO-A and hMAO-B in the submicromolar range, with Jas2 and Jas6 showing the highest MAO-B selectivity indices. At 100 µM, the series produced mild but significant pro-oxidant and cytotoxic effects when applied alone, yet under oxidative stress all compounds, especially Jas2 and Jas6, markedly preserved synaptosomal and mitochondrial viability, maintained glutathione levels, and reduced malondialdehyde production. Conclusions: The caffeine-based semi- and thiosemicarbazides, particularly Jas2 and Jas6, emerge as promising selective MAO-B inhibitors with pronounced antioxidant and neuroprotective activity, supporting their further optimization as multitarget candidates for neurodegenerative disorders such as Parkinson’s disease. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by the accumulation of the toxic protein amyloid-β, formation of tau-containing neurofibrillary tangles, neuroinflammation, and synaptic dysfunction, highlighting the need for new therapeutic strategies capable of modulating multiple pathological pathways simultaneously. In this study, a structure-based in silico approach was applied to evaluate the multi-target potential of two previously reported pyrrole-based compounds (pyrrole 1 and pyrrole 2) with known monoamine oxidase-B (MAO-B) inhibitory activity and low neurotoxicity. Molecular docking studies were performed against a panel of key AD-related targets, including GSK-3β, APP, MAO-B, BACE1, AChE, BChE, COX-2, GABA-B receptor, NMDA receptor, and E3 ubiquitin ligase CHIP, using Glide XP docking. The results revealed that compound pyrrole 1 may have favorable predicted binding affinities across several targets, with relatively strong docking scores for GSK-3β and COX-2. The binding mode analysis indicated that pyrrole 1 adopts poses consistent with interaction patterns commonly observed for ATP-competitive GSK-3β inhibitors and COX-2 ligands. In silico ADMET profiling using the software SwissADME and ProTox 3.0 indicated distinct pharmacokinetic and safety profiles for the two compounds, with pyrrole 2 showing superior drug-likeness and predicted blood–brain barrier penetration, while pyrrole 1 displayed a more favorable overall toxicity profile. Collectively, these findings identify pyrrole 1 as a theoretically promising multi-target candidate for AD requiring experimental validation, while providing a strong structural basis for further optimizations and subsequent experimental confirmation. Full article

Depression is increasingly linked to microbiota–gut–brain axis dysfunction, yet current monoaminergic antidepressants show limited efficacy. This study investigated the therapeutic potential and underlying mechanisms of GV-971, a marine-derived oligosaccharide, in a chronic restraint stress (CRS) mouse model. We first established that 8 h of daily restraint for 4–8 weeks induces a stable depression-like phenotype characterized by behavioral despair and significant reduction in peripheral monoamine neurotransmitters (5-HT and norepinephrine). GV-971 treatment robustly attenuated CRS-induced depression- and anxiety-like behaviors, restored hippocampal serotonin levels, reduced elevated plasma corticosterone concentrations, and ameliorated CRS-induced adrenal cortical hyperplasia. Mechanistically, GV-971 significantly suppressed neuroinflammation by inhibiting microglial hyperactivation in the prefrontal cortex and hippocampus. Concurrently, it repaired intestinal barrier dysfunction, evidenced by reduced permeability, restored mucosal integrity, and recovered goblet cell numbers. Crucially, integrated shot-gun metagenomics and plasma metabolomics revealed that GV-971 not only reshaped microbial taxonomy but also functionally recalibrated the gut ecosystem. It enriched beneficial taxa (e.g., Bifidobacterium pseudolongum, Bacteroides uniformis) and specific metabolic pathways, leading to increased short-chain fatty acids (valeric and caproic acids) and a significant reduction in plasma levels of tryptophan–kynurenine pathway metabolites, specifically the neurotoxic compounds kynurenine and quinolinic acid. Fecal microbiota transplantation (FMT) from GV-971-treated donors partially recapitulated the antidepressant and gut-protective effects in CRS recipients, confirming a causal role for the remodeled microbiota. Collectively, GV-971 exerts antidepressant effects by coordinately remodeling the gut microbiota, normalizing tryptophan and SCFA metabolism, restoring gut barrier integrity, and dampening central neuroinflammation, supporting its potential as a novel gut–brain axis-targeted therapy for depression. Full article

The effects of antidepressants on limbic structures, important in the context of the treatment of Parkinson’s disease (PD)-associated depression, are relatively poorly explored in animal models. The present study investigated the impact of the tricyclic antidepressant amitriptyline (AMI), administered chronically alone or in combination with L-DOPA, on anhedonia, monoamine levels, and the binding of radioligands to their transporters in the limbic structures of unilaterally 6-OHDA-lesioned rats. Anhedonia, as a core symptom of depression, was evaluated using the sucrose preference test. Tissue concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) and their metabolites in the prefrontal cortex (PFC) and hippocampus (HIP) were assayed by HPLC method. Bindings of [³H]nisoxetine to noradrenaline transporter (NET), [³H]GBR 12,935 to dopamine transporter (DAT), and [³H]citalopram to serotonin transporter (SERT) in the nucleus accumbens (NAcc), PFC, and HIP were analyzed by autoradiography. Three weeks of treatment of unilaterally 6-OHDA-lesioned rats with AMI alone significantly reduced the intake of sucrose solution compared to the sham-operated control, but the combined administration of AMI+L-DOPA enhanced sucrose consumption. Administration of AMI+L-DOPA increased tissue DA concentrations in the lesioned and intact PFC and HIP more distinctly than L-DOPA alone. L-DOPA alone significantly decreased tissue 5-HT content in the lesioned PFC and HIP, while the addition of AMI reversed this effect. 6-OHDA administered unilaterally into the MFB drastically decreased DAT binding in the lesioned NAcc while increasing it on the intact side. Neither AMI nor L-DOPA, given alone or jointly, affected DAT binding in the lesioned NAcc. SERT binding was significantly reduced in the PFC, NAcc and HIP on both sides of the brain in the AMI- or AMI+L-DOPA-treated groups. NET binding decreased in the PFC and NAcc in the AMI-treated group, but no such effect was observed in the AMI+L-DOPA-treated group. The obtained results are discussed in relation to the impaired psychiatric functions in PD. Full article

Background: Nutritional psychiatry increasingly links diet quality and specific bioactive nutrients to depression and anxiety outcomes. Mechanistic evidence implicates neuroimmune activation, inflammation, altered neurotransmitter synthesis, and microbiota-derived metabolites. Objective: The objective of this study is to synthesize evidence on omega-3 polyunsaturated fatty acids (n-3 PUFAs), the microbiota–gut–brain axis, and vitamins and minerals that influence neurotransmitter synthesis, inflammation, and brain function and to translate these findings into food-based strategies. Methods: This study consisted of a focused synthesis of randomized controlled trials (RCTs), meta-analyses, and systematic reviews indexed in PubMed, Scopus and Web of Science, selected for relevance to omega-3s, probiotics/prebiotics, dietary patterns, and micronutrients (folate/B-vitamins, vitamin D, magnesium, zinc, and vitamin C/copper pathways). Results: RCT and meta-analytic evidence suggest modest benefits of omega-3 supplementation for anxiety severity and depressive symptoms, with heterogeneity by dose, EPA: DHA composition, and baseline inflammatory status. The gut–brain axis literature supports bidirectional effects of stress and microbiota, and meta-analyses of probiotics/prebiotics show small improvements in depressive and anxiety symptoms, likely dependent on strain and host phenotype. Micronutrients serve as enzymatic cofactors for monoamine and GABA synthesis and modulate immune signaling; clinical effects are the most consistent when correcting insufficiency or in biomarker-defined subgroups. A whole-diet RCT demonstrates that structured dietary improvement can reduce depressive symptoms as adjunctive therapy. Conclusions: A food-first approach emphasizing Mediterranean-style dietary patterns, omega-3-rich seafood, a diverse array of fiber, and micronutrient density is the most defensible. Supplementation may be considered selectively, guided by clinical context and nutritional status. Full article

Objective: ZhiZhu Kuanzhong (ZZKZ) capsule, a Chinese herbal extract, is extensively employed for the clinical management of functional dyspepsia (FD) in China. This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of ZZKZ on the co-morbidity of anxiety and depression of FD. Methods: The FD model was established in Sprague–Dawley rats via neonatal gastric irritation with 0.1% iodoacetamide. Subsequently, FD rats were gavaged with ZZKZ or fluoxetine. Depression-like behaviors were evaluated using the sucrose preference test (SPT) and forced swimming test (FST), while anxiety-like behaviors were assessed via light-dark box (LDB) and open field tests (OFTs). Network pharmacology and molecular docking were conducted to explore the mechanisms of ZZKZ’s action. Hippocampal levels of monoamine neurotransmitters and monoaminergic system components were evaluated by HPLC and RT-qPCR, respectively. Serum concentrations of HPA axis hormones were determined by ELISA. Results: ZZKZ administration reversed the deficits in body weight gain and food intake in FD rats. Behaviorally, ZZKZ increased sucrose consumption in SPT and prolonged swimming duration in FST, and it increased duration and entries into the central zone in OFT. According to the prediction of network pharmacology, ZZKZ treatment elevated hippocampal levels of 5-HT/NE/DA, increased expression of TPH2/TH, and decreased expression of MAO_A/SERT in FD rats. Molecular docking further confirmed high-affinity binding between core ingredients of ZZKZ and TPH2/TH/MAO_A/SERT. Moreover, ZZKZ administration attenuated the stress-induced elevation of serum CRH/ACTH/CORT. Conclusions: ZZKZ effectively ameliorates the disordered gut–brain interaction and mitigates anxiety-like and depression-like behaviors, which might be modulated by the hippocampal monoaminergic system and hypothalamic–pituitary–adrenal axis response. Full article

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by progressive motor and non-motor manifestations, including early gastrointestinal dysfunction. Growing evidence implicates the gut microbiota as an active modulator of host immune tone and neurodegenerative vulnerability, extending beyond descriptive taxonomic associations toward functional and metabolic mechanisms. PD-associated dysbiosis is consistently characterized by altered microbial functional capacity, including reduced short-chain fatty acid (SCFA) production, enrichment of pro-inflammatory metabolic traits, and sustained immune stimulation at the intestinal interface. These shifts promote chronic low-grade inflammation and intestinal barrier perturbations, creating conditions that may facilitate abnormal α-synuclein aggregation within the enteric nervous system. Current management predominantly relies on dopaminergic replacement and related symptomatic strategies, such as levodopa combinations, dopamine agonists, monoamine oxidase-B and catechol-O-methyltransferase (COMT) inhibitors, and device-aided therapies, which alleviate symptoms but do not halt underlying neurodegeneration or modify long-term disease course. These therapeutic limitations have intensified interest in upstream mechanisms that might be amenable to disease-modifying interventions, particularly those arising at the level of the gut microbiota and gut–immune–brain axis. This narrative review integrates clinical, metagenomic, metabolomic, and mechanistic evidence to propose a unified model in which microbiota-driven immune and metabolic perturbations may act as upstream drivers converging on α-synuclein pathology, neuroinflammation, and neurovascular dysfunction. Full article

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

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

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

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/Objectives: Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer. Methods: In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo. Results: These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood–brain barrier, while exhibiting low toxicity in healthy cells. Conclusions: In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma. Full article

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as “susto” (fright) or “espanto” (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract’s effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD₅₀ was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression. Full article

Background: Virtual screening is a widely adopted technique for the discovery of novel pharmacologically active compounds; however, the risk of identifying false positive hits remains a major challenge. Aim: The aim of this study was to perform a validated structure-based drug design screening to discover multitarget pyrrole-based molecules as selective dual-acting monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors. Methods: The study employed validated docking protocols using Glide (Schrödinger) and GOLD (CCDC), integrating ligand enrichment analysis and robust Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring. These methods were applied to a custom-designed database of pyrrole-based compounds. The top-ranked hits were synthesized and validated through in vitro tests, demonstrating significant inhibitory activities against MAO-A, MAO-B, AChE, and Butyrylcholinesterase (BChE). Results: The docking protocols achieved favorable hit rates, with 25.93% for AChE inhibitors and 44.44% for MAO-B inhibitors. Additionally, structure–activity relationship analysis revealed key substituent effects that significantly influence binding affinity and selectivity. Two compounds, EM-DC-19 (2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2H-imidazol-4-yl)propanoic acid) and EM-DC-27 ([4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]acetic acid), were identified as selective MAO-B inhibitors with additional moderate AChE inhibitory activity, demonstrating IC₅₀ values of 0.299 ± 0.10 µM and 0.344 ± 0.10 µM against MAO-B, and 76.15 ± 6.12 µM and 375.20 ± 52.99 µM against AChE, respectively. The absence of statistically significant inhibitory effects of these lead compounds on MAO-A and BChE (IC₅₀ > 100 µM) underscores their selective inhibitory activity towards MAO-B and AChE. Furthermore, both compounds demonstrated low neurotoxicity and significant neuroprotective and antioxidant effects in rat brain synaptosomes, mitochondria, and microsomes. These effects were particularly evident in models of 6-hydroxydopamine-induced neurotoxicity (6-OHDA) and oxidative stress induced by tert-butyl hydroperoxide and Fe²⁺/ascorbic acid. Conclusions: The findings suggest that these multitarget compounds hold promise for further development, with potential for structural modifications to enhance their enzyme inhibitory and neuroprotective properties. Full article