Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin-Sulfonamide-Nitroindazolyl-Triazole Hybrids as Monoamine Oxidase Inhibitors.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

Genetics of child aggression, a systematic review.

Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.

Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.

Antidepressant-like Effects of Chinese Quince (Chaenomeles sinensis) Fruit Based on In Vivo and Molecular Docking Studies.

In this study, we examined the potential antidepressant-like effects of Chinese quince fruit extract (Chaenomeles sinensis fruit extract, CSFE) in an in vivo model induced by repeated injection of corticosterone (CORT)-induced depression. HPLC analysis determined that chlorogenic acid (CGA), neo-chlorogenic acid (neo-CGA), and rutin (RT) compounds were major constituents in CSFE. Male ICR mice (5 weeks old) were orally administered various doses (30, 100, and 300 mg/kg) of CSFE and selegiline (10 mg/kg), a monoamine oxidase B (MAO-B) inhibitor, as a positive control following daily intraperitoneal injections of CORT (40 mg/kg) for 21 days. In our results, mice treated with CSFE exhibited significant improvements in depressive-like behaviors induced by CORT. This was evidenced by reduced immobility times in the tail suspension test and forced swim test, as well as increased step-through latency times in the passive avoidance test. Indeed, mice treated with CSFE also exhibited a significant decrease in anxiety-like behaviors as measured by the elevated plus maze test. Moreover, molecular docking analysis indicated that CGA and neo-CGA from CSFE had stronger binding to the active site of MAO-B. Our results indicate that CSFE has potential antidepressant effects in a mouse model of repeated injections of CORT-induced depression.

Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed.

A versatile family of quaternary propargylamines was synthesized employing the KA2 multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC50 values for hMAO-B range from 152.1 to 164.7 nM while the IC50 values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.

Non-Synonymous Substitutions in Cadherin 13, Solute Carrier Family 6 Member 4, and Monoamine Oxidase A Genes are Associated with Personality Traits in Thoroughbred Horses.

Retraining retired racehorses for various purposes can help correct behavioral issues. However, ensuring efficiency and preventing accidents present global challenges. Based on the hypothesis that a simple personality assessment could help address these challenges, the present study aimed to identify genetic markers associated with personality. Eight genes were selected from 18 personality-related candidate genes that are orthologs of human personality genes, and their association with personality was verified based on actual behavior. A total of 169 Thoroughbred horses were assessed for their tractability (questionnaire concerning tractability in 14 types of situations and 3 types of impressions) during the training process. Personality factors were extracted from the data using principal component analysis and analyzed for their association with single nucleotide variants as non-synonymous substitutions in the target genes. Three genes, CDH13, SLC6A4, and MAOA, demonstrated significant associations based on simple linear regression, marking the identification of these genes for the first time as contributors to temperament in Thoroughbred horses. All these genes, as well as the previously identified HTR1A, are involved in the serotonin neurotransmitter system, suggesting that the tractability of horses may be correlated with their social personality. Assessing the genotypes of these genes before retraining is expected to prevent problems in the development of a racehorse's second career and shorten the training period through individual customization of training methods, thereby improving racehorse welfare.

Ramelteon protects against social defeat stress-associated abnormal behaviors.

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.

Effects of selegiline on neuronal autophagy involving α-synuclein secretion.

Cell-to-cell transmission of α-synuclein (α-syn) pathology underlies the spread of neurodegeneration in Parkinson's disease. α-Syn secretion is an important factor in the transmission of α-syn pathology. However, it is unclear how α-syn secretion is therapeutically modulated. Here, we investigated effects of monoamine oxidase (MAO)-B inhibitor selegiline on α-syn secretion. Treatment with selegiline promoted α-syn secretion in mouse primary cortical neuron cultures, and this increase was kept under glial cell-eliminated condition by Ara-C. Selegiline-induced α-syn secretion was blocked by cytosolic Ca2+ chelator BAPTA-AM in primary neurons. Selegiline-induced α-syn secretion was retained in MAOA siRNA knockdown, whereas it was abrogated by ATG5 knockdown in SH-SY5Y cells. Selegiline increased LC3-II generation with a reduction in intracellular p62/SQSTM1 levels in primary neurons. The increase in LC3-II generation was blocked by co-treatment with BAPTA-AM in primary neurons. Additionally, fractionation experiments showed that selegiline-induced α-syn secretion occurred in non-extracellular vesicle fractions of primary neurons and SH-SY5Y cells. Collectively, these findings show that selegiline promotes neuronal autophagy involving secretion of non-exosomal α-syn via a change of cytosolic Ca2+ levels.

Proteomic profiling of renal tissue of normo- and hypertensive rats with the renalase peptide RP220 as an affinity ligand.

Renalase (RNLS) is a recently discovered protein that plays an important role in the regulation of blood pressure by acting inside and outside cells. Intracellular RNLS is a FAD-dependent oxidoreductase that oxidizes isomeric forms of ß-NAD(P)H. Extracellular renalase lacking its N-terminal peptide and cofactor FAD exerts various protective effects via non-catalytic mechanisms. Certain experimental evidence exists in the literature that the RP220 peptide (a 20-mer peptide corresponding to the amino acid sequence RNLS 220-239) reproduces a number of non-catalytic effects of this protein, acting on receptor proteins of the plasma membrane. The possibility of interaction of this peptide with intracellular proteins has not been studied. Taking into consideration the known role of RNLS as a possible antihypertensive factor, the aim of this study was to perform proteomic profiling of the kidneys of normotensive and hypertensive rats using RP220 as an affinity ligand. Proteomic (semi-quantitative) identification revealed changes in the relative content of about 200 individual proteins in the kidneys of hypertensive rats bound to the affinity sorbent as compared to the kidneys of normotensive animals. Increased binding of SHR renal proteins to RP220 over the normotensive control was found for proteins involved in the development of cardiovascular pathology. Decreased binding of the kidney proteins from hypertensive animals to RP220 was noted for components of the ubiquitin-proteasome system, ribosomes, and cytoskeleton.

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

Towards cost-effective drug discovery: Reusable immobilized enzymes for neurological disease research.

Enzyme handling and utilization bears many challenges such as their limited stability, intolerance of organic solvents, high cost, or inability to reuse. Most of these limitations can be overcome by enzyme immobilization on the surface of solid support. In this work, the recombinant form of human cholinesterases and monoamine oxidases as important drug targets for neurological diseases were immobilized on the surface of magnetic non-porous microparticles by a non-covalent bond utilizing the interaction between a His-tag terminus on the recombinant enzymes and cobalt (Co2+) ions immobilized on the magnetic microparticles. This type of binding led to targeted enzyme orientation, which completely preserved the catalytic activity and allowed high reproducibility of immobilization. In comparison with free enzymes, the immobilized enzymes showed exceptional stability in time and the possibility of repeated use. Relevant Km, Vmax, and IC50 values using known inhibitors were obtained using particular immobilized enzymes. Such immobilized enzymes on magnetic particles could serve as an excellent tool for a sustainable approach in the early stage of drug discovery.

Dihydroxanthene-based monoamine oxidase A-activated photosensitizers for photodynamic/photothermal therapy of tumors.

Small molecule photosensitizers for combined in vivo tailored cancer diagnostics and photodynamic/photothermal therapy are desperately needed. Monoamine oxidase A (MAO-A)-activated therapeutic and diagnostic compounds provide great selectivity because MAO-A can be employed as a biomarker for associated Tumors. In order to screen photosensitizers with photodynamic therapeutic potential, we have created a range of near-infrared fluorescent molecules in this work by combining dihydroxanthene parent with various heterocyclic fluorescent dyes. The NIR fluorescent diagnostic probe, DHMQ, was created by combining the screened fluorescent dye matrices with the propylamino group, which is the recognition moiety of MAO-A, based on the oxidative deamination mechanism of the enzyme. This probe has a low toxicity level and can identify MAO-A precisely. It has the ability to use fluorescence imaging on mice and cells to track MAO-A activity in real-time. It has strong phototoxicity and can produce singlet oxygen when exposed to laser light. The temperature used in photothermal imaging can get up to 50 °C, which can harm tumor cells permanently and have a positive phototherapeutic impact on tumors grown from SH-SY5Y xenograft mice. The concept of using MAO-A effectively in diseases is expanded by the MAO-A-activated diagnostic-integrated photosensitizers, which offer a new platform for in vivo cancer diagnostics and targeted anticancer treatment.

Enantiodivergent kinetic resolution of 4-substituted 1,2,3,4-tetrahydroquinolines employing amine oxidase.

Optically pure 1,2,3,4-tetrahydroquinolines (THQs) represent a class of important motifs in many natural products and pharmaceutical agents. While recent advances on redox biocatalysis have demonstrated the great potential of amine oxidases, all the transformations focused on 2-substituted THQs. The corresponding biocatalytic method for the preparation of chiral 4-substituted THQs is still challenging due to the poor activity and stereoselectivity of the available enzyme. Herein, we developed a biocatalytic kinetic resolution approach for enantiodivergent synthesis of 4-phenyl- or alkyl-substituted THQs. Through structure-guided protein engineering of cyclohexylamine oxidase derived from Brevibacterium oxidans IH-35 A (CHAO), the variant of CHAO (Y215H/Y214S) displayed improved specific activity toward model substrate 4-phenyl substituted THQ (0.14 U/mg, 13-fold higher than wild-type CHAO) with superior (R)-stereoselectivity (E > 200). Molecular dynamics simulations show that CHAO Y215H/Y214S allows a suitable substrate positioning in the expanded binding pocket to be facilely accessed, enabling enhanced activity and stereoselectivity. Furthermore, a series of 4-alkyl-substituted THQs can be transformed by CHAO Y215H/Y214S, affording R-isomers with good yields (up to 50 %) and excellent enantioselectivity (up to ee > 99 %). Interestingly, the monoamine oxidase from Pseudomonas fluorescens Pf0-1 (PfMAO1) with opposite enantioselectivity was also mined. Together, this system enriches the kinetic resolution methods for the synthesis of chiral THQs.

Tonic excitation by astrocytic GABA causes neuropathic pain by augmenting neuronal activity and glucose metabolism.

Neuropathic pain is a debilitating condition caused by the hyperexcitability of spinal dorsal horn neurons and is often characterized by allodynia. Although neuron-independent mechanisms of hyperexcitability have been investigated, the contribution of astrocyte-neuron interactions remains unclear. Here, we show evidence of reactive astrocytes and their excessive GABA release in the spinal dorsal horn, which paradoxically leads to the tonic excitation of neighboring neurons in a neuropathic pain model. Using multiple electrophysiological methods, we demonstrated that neuronal hyperexcitability is attributed to both increased astrocytic GABA synthesis via monoamine oxidase B (MAOB) and the depolarized reversal potential of GABA-mediated currents (EGABA) via the downregulation of the neuronal K+/Cl- cotransporter KCC2. Furthermore, longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET imaging demonstrated increased regional glucose metabolism in the ipsilateral dorsal horn, reflecting neuronal hyperexcitability. Importantly, inhibiting MAOB restored the entire astrocytic GABA-mediated cascade and abrogated the increased glucose metabolism and mechanical allodynia. Overall, astrocytic GABA-mediated tonic excitation is critical for neuronal hyperexcitability, leading to mechanical allodynia and neuropathic pain.

Non-cytotoxic 3-Acetylcoumarin as an Attractive Target for Human Monoamine Oxidase (HMAO) Enzymes.

BACKGROUND/AIM: Coumarins are a broad class of naturally occurring oxygen-heterocyclic compounds found in plants with diverse biological properties, making them attractive for evaluation as novel therapeutic agents. We herein report the in vitro cytotoxic and monoamine oxidase (MAO) inhibitory activities of 3-acetylcoumarins (6a-e). MATERIALS AND METHODS: The cytotoxic activity was evaluated using crystal violet dye binding assay, and those compounds unable to induce cytotoxicity were further tested for the monoamine oxidase (MAO) activity using the MAO-GloTM kit. RESULTS: The 3-acetylcoumarins (6a-e) were non-cytotoxic (inactive) against MDA MB-231 (estrogen receptor-negative, ER-, highly invasive) and MCF-7 (estrogen receptor-positive, ER+, weakly invasive) breast cancer cell lines, but showed interesting MAOs inhibition activities. Among the synthesized compounds, 3-acetylcoumarin bearing dichloro (-diCl) (6d; IC50=0.31±0.04 µM) at Carbon-7, 8 positions showed higher inhibition, MAO B/A non-selectivity (selectivity index, SI=3.10), reversible inhibition against the hMAO-B enzyme, and neuroprotection against H2O2-treated human neuroblastoma (N2a) cells. CONCLUSION: Compound (6d) can be considered a promising scaffold for further investigation in developing hMAO-B inhibitors (MAOIs).

Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease.

Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 µM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.

Baicalin and baicalein from Scutellaria baicalensis Georgi alleviate aberrant neuronal suppression mediated by GABA from reactive astrocytes.

AIMS: γ-aminobutyric acid (GABA) from reactive astrocytes is critical for the dysregulation of neuronal activity in various neuroinflammatory conditions. While Scutellaria baicalensis Georgi (S. baicalensis) is known for its efficacy in addressing neurological symptoms, its potential to reduce GABA synthesis in reactive astrocytes and the associated neuronal suppression remains unclear. This study focuses on the inhibitory action of monoamine oxidase B (MAO-B), the key enzyme for astrocytic GABA synthesis. METHODS: Using a lipopolysaccharide (LPS)-induced neuroinflammation mouse model, we conducted immunohistochemistry to assess the effect of S. baicalensis on astrocyte reactivity and its GABA synthesis. High-performance liquid chromatography was performed to reveal the major compounds of S. baicalensis, the effects of which on MAO-B inhibition, astrocyte reactivity, and tonic inhibition in hippocampal neurons were validated by MAO-B activity assay, qRT-PCR, and whole-cell patch-clamp. RESULTS: The ethanolic extract of S. baicalensis ameliorated astrocyte reactivity and reduced excessive astrocytic GABA content in the CA1 hippocampus. Baicalin and baicalein exhibited significant MAO-B inhibition potential. These two compounds downregulate the mRNA levels of genes associated with reactive astrogliosis or astrocytic GABA synthesis. Additionally, LPS-induced aberrant tonic inhibition was reversed by both S. baicalensis extract and its key compounds. CONCLUSIONS: In summary, baicalin and baicalein isolated from S. baicalensis reduce astrocyte reactivity and alleviate aberrant tonic inhibition of hippocampal neurons during neuroinflammation.

Caffeic acid attenuates memory dysfunction and restores the altered activity of cholinergic, monoaminergic and purinergic in brain of cadmium chloride exposure rats.

OBJECTIVES: This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity. METHODS: The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3 mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20 mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20 mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index. RESULTS: CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20 mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF. CONCLUSIONS: This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats.