MAO-B Activity Research Articles

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems.

Effects of diphenyl diselenide on behavioral and biochemical changes induced by amphetamine in mice.

Diphenyl diselenide (PhSe)2, an organoselenium compound, has been studied as a potential pharmacological agent in different in vitro and in vivo models, mainly due to its antioxidant properties. However, there are few studies concerning the effects of (PhSe)2 on dopaminergic system. Thus, the purpose of the present study was to evaluate the effects of acute and sub-chronic treatment of (PhSe)2 on amphetamine-induced behavioral and biochemical parameters. In acute protocol, mice were pre-treated with 5 or 10 mg/kg of (PhSe)2 and 30 min after, amphetamine was administered. In sub-chronic protocol, mice were pre-treated with 5 or 10 mg/kg of (PhSe)2 during 7 days and 24 h after, amphetamine was administered. Twenty-five minutes after amphetamine administration, behavioral (crossing, rearing, time of stereotypy and immobility) and biochemical (MAO activity, DCFH-DA oxidation, protein and non-protein thiol groups) parameters were analyzed. Amphetamine increased the number of crossing and rearing and (PhSe)2 prevented only the increase in the number of crossings when acutely administered to mice. Furthermore, amphetamine increased stereotypy and time of immobility in mice. (PhSe)2, at 10 mg/kg, increased per se the stereotypy and time of immobility when sub-chronically administered. (PhSe)2, at 10 mg/kg, potentiated the stereotypy caused by amphetamine in both protocols. Sub-chronic treatment with (PhSe)2 either alone (5 and 10 mg/kg) or in combination (10 mg/kg) with amphetamine decreased brain MAO-B activity. Oxidative stress parameters were not modified by (PhSe)2 and/or amphetamine treatments. In conclusion, sub-chronic administration of (PhSe)2 can promote a behavioral sensitization that seems to be, at least in part, dependent of MAO-B inhibition.

Hepatocyte Transplants Improve Liver Function and Encephalopathy in Portacaval Shunted Rats

Rats with portacaval shunt (PCS) are useful experimental models of human hepatic encephalopathy in chronic liver dysfunction. We have previously shown that PCS modifies amine neurotransmitter systems in the CNS and increases voluntary alcohol intake by rats. Hepatocyte transplantation, used in acute liver failure, has recently also been applied to chronic liver diseases, which prompted us to investigate whether the altered brain amine system and the drinking behavior in long-term shunted rats could be normalized by hepatocyte transplants. Hepatocytes, isolated from syngeneic donors by collagenase digestion, were injected (3 × 10(6) cells/rat) into the pancreatic tail region, 6 months after PCS. Hepatic function was evaluated by measuring urine urea and plasma L-histidine concentrations. A free choice test with two bottles (tap water and 10% ethyl alcohol) was performed for 3 days to assess the rats' preference for alcohol. The rats were euthanized 2 months posttransplantation. Brain histamine and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured by radioenzymatic assay and by HPLC-EC, respectively, N-tele-methylhistamine by GC/MS while MAOA and MAOB activities by isotopic procedures. Portacaval shunt rats with hepatocyte transplants gave more urea than before transplantation, with lower plasma L-His levels and higher body weight versus the PCS counterparts. Also, those rats consumed less alcohol. The CNS amines and 5-HIAA concentrations, as well as MAO-B activity, being abnormally high in untreated PCS rats, significantly reduced after PCS hepatocyte treatment. The results support the therapeutic values of hepatocyte transplants in chronic liver diseases and the temporary character of PCS-exerted CNS dysfunctions.

Compounds in Psoralea corylifolia as human MAOb natural inhibitors (1143.12)

Treatment for Parkinson’s disease (PD) involves the use of drugs that address the loss of dopaminergic function by restoring neurotransmitter homeostasis. However, the current drugs can be limiting, in that they do not address disease progression. A renewed interest in monoamine oxidase B inhibitors (MAObIs) for PD as independent therapeutics has emerged after recent clinical trials has shown efficacy of deprenyl and rasagiline monotherapy for early disease management. However, conventional MAOIs have food and drug counter‐interactions and side effects which limit its use. Previously, we screened 905 natural ethanol plant extracts on the enzymatic activity of recombinant human MAOb. In this study, we confirm and determine selectivity of MAOb / MAOa. The data show that extracts of Glycyrrhiza uralensis root have an IC50 of 0.04 mg/ml and a 266 fold MAOb/MAOa specificity; Phellodendron Amurense an IC50 of 0.02 mg/ml and a MAOb/MAOa specificity 45.29 fold; Psoralea Corylifolia (PC) an IC50 of 0.08 mg/ml and a 18.34 fold MAOb/MAOa specificity; Ferula Assa‐Foetida an IC50 of 0.24 mg/ml and a 30.23 fold MAOb/MAOa specificity. Further studies for PC active ingredients revealed that bakuchiol content within the plant may contribute to MAOI.Grant Funding Source: Supported by NIMHD G12 MD007582 and P20 MD006738

Selective monoamine oxidase B inhibition by an Aphanizomenon flos-aquae extract and by its constitutive active principles phycocyanin and mycosporine-like amino acids

Aphanizomenon flos-aquae (AFA) is a fresh water unicellular blue-green alga that has been traditionally used for over 25 years for its health-enhancing properties. Recent studies have shown the ability of a proprietary AFA extract (Klamin®) to improve mood, counteract anxiety, and enhance attention and learning. Aim of this study was to test the monoamine oxidase (MAO) inhibition activity of the same AFA extract and of its constituents phycocyanin (AFA-PC) and mycosporine-like aminoacids (AFA-MAAs). All compounds showed a dose-dependent selective inhibition of MAO-B activity as compared to MAO-A. The IC50 values of the AFA extract (concentration 10mg/ml), AFA-PC and AFA-MAAs were 6.4μl/ml, 1.33μM and 1.98μM, respectively, evidencing a mixed-type of inhibition for the AFA extract (Ki 0.99μl/ml), a non-competitive inhibition for AFA-PC (Ki 1.06μM) and a competitive inhibition for AFA-MAAs (Ki 0.585μM). These results are important to explain the neuromodulating properties of the AFA extract Klamin®, which is rich in phenylethylamine, a general neuromodulator, that would nevertheless rapidly destroyed by MAO-B enzymes without the inhibitory activity of the synergic active principles AFA-PC and AFA-MAAs. The present investigation thus proposes the extract as potentially relevant in clinical areas such as mood disorders and neurodegenerative diseases.

Synthesis, Pharmacological Study and Docking Calculations of New Benzo[ f ]coumarin Derivatives as Dual Inhibitors of Enzymatic Systems Involved in Neurodegenerative Diseases

Due to the complex etiology of neurodegenerative diseases, there is growing interest in multitarget drugs. In this study we synthesized and evaluated a new series of compounds, with benzo[f]coumarin structure, as potential inhibitors of MAO-A, MAO-B, AChE and BuChE. In vitro studies show that most of the studied compounds inhibited the activity of MAO-B in the nano- to micro-molar range. 3-(3´-methoxyphenyl)benzo[f]coumarin is the most active compound with an IC50 value against MAO-B of 2.44 nM. Most of the derivatives exhibited an important selectivity profile against the MAO-B isoform. Some of them also acted as in vitro inhibitors of BuChE, with 3-(2´-hydroxyphenyl)benzo[f]coumarin being the most active with an IC50 value of 1.13 µM. In addition, a theoretical study of the physicochemical properties of the new compounds, as well as a docking study in both MAO isoforms, were carried out. Important structure-activity relationships were obtained. Important preliminary structure-activity relationships were concluded from the experimental results. These results encourage us to further explore the potential of this chemical family as potential drug candidates for the treatment of Alzheimer's disease.

Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system

Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels.

A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson’s disease models

The unusually high MAO-B activity consistently observed in Parkinson's disease (PD) patients has been proposed as a biomarker; however, this has not been realized due to the lack of probes suitable for MAO-B-specific detection in live cells/tissues. Here we report the first two-photon, small molecule fluorogenic probe (U1) that enables highly sensitive/specific and real-time imaging of endogenous MAO-B activities across biological samples. We also used U1 to confirm the reported inverse relationship between parkin and MAO-B in PD models. With no apparent toxicity, U1 may be used to monitor MAO-B activities in small animals during disease development. In clinical samples, we find elevated MAO-B activities only in B lymphocytes (not in fibroblasts), hinting that MAO-B activity in peripheral blood cells might be an accessible biomarker for rapid detection of PD. Our results provide important starting points for using small molecule imaging techniques to explore MAO-B at the organism level.

Influence of Altered Hormonal Status on Platelet 5-HT and MAO-B Activity in Cigarette Smokers.

The present study was designed to understand the cigarette smoking-induced alterations in hormones and the resulting changes in platelet serotonin (5-hydroxytryptamine, 5-HT) and monoamine oxidase (MAO-B) activity in chronic smokers. Human male volunteers aged 35±8years, were divided into two groups, namely controls and smokers (12±2 cigarettes per day for 7-10years). Results showed that cigarette smoking significantly (p<0.05) elevated plasma triiodothyronine (T3), cortisol and testosterone levels with significant (p<0.05) reduction in plasma tryptophan and thyroxin (T4). Moreover, smokers showed reduced platelet 5-HT levels and MAO-B activity. In smokers, plasma cortisol was negatively correlated with tryptophan (r=-0.386), platelet MAO-B (r=-0.264), and 5-HT (r=-0.671), and positively correlated with testosterone (r=0.428). However, testosterone was negatively correlated with platelet MAO-B (r=-0.315), and 5-HT (r=-.419) in smokers. Further, smokers plasma T3 levels were negatively correlated with platelet MAO-B (r=-0.398), and 5-HT (r=-0.541), whereas T4 levels were positively correlated with platelet MAO-B (r=0.369), and 5-HT (r=0.454). In conclusion, our study showed that altered testosterone and cortisol levels may aggravate behavior, mood disturbances and symptoms of depression by decreasing platelet 5-HT and MAO-B activity in smokers.

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

Altered Monoamine Metabolism in High Fat Diet Induced Neuropsychiatric Changes in Rats

Objective: To investigate the role of central and peripheral monoamine metabolism on neuropsychological status in high fat diet induced obese rats. Method: Animals were fed on high fat diet for 12 weeks. Periodically blood was collected to estimate serum Metanephrine (MN) levels. After 11 weeks, behavioural paradigms of depression, locomotor activity and cognition were performed. Central (brain) and peripheral i.e. Visceral White Adipose Tissue (vWAT) and Brown Adipose Tissue (BAT) MN levels, Monoamine Oxidase A and B (MAO-A, MAO-B) enzyme activity and Acetylcholinesterase (AChE) activity was estimated. Results: High fat diet significantly increased the body weight which was negatively correlated with the serum metanephrine concentration. However, metanephrine concentration in brain was significantly decreased whereas it significantly increased in vWAT with no change in BAT. In obese animals, immobility time in forced swim test and transfer latency in elevated plus maze was significantly increased while locomotor activity was significantly decreased. Central MAO-A and MAO-B activities were increased while enzyme activities showed a significant reduction in vWAT with no change in BAT. Brain AChE activity was also increased significantly in obese rats. Conclusion: Metabolism of biogenic monoamines plays a critical role in altered neuropsychiatric behaviours associated with diet induced obesity.

Selective MAO-B inhibitors: a lesson from natural products

Monoamine oxidases (MAOs) are mitochondrial bound enzymes, which catalyze the oxidative deamination of monoamine neurotransmitters. Inside the brain, MAOs are present in two isoforms: MAO-A and MAO-B. The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's. Therefore, the search for potent and selective MAO-B inhibitors is still a challenge for medicinal chemists. Nature has always been a source of inspiration for the discovery of new lead compounds. Moreover, natural medicine is a major component in all traditional medicine systems. In this review, we present the latest discoveries in the search for selective MAO-B inhibitors from natural sources. For clarity, compounds have been classified on the basis of structural analogy or source: flavonoids, xanthones, tannins, proanthocyanidins, iridoid glucosides, curcumin, alkaloids, cannabinoids, and natural sources extracts. MAO inhibition values reported in the text are not always consistent due to the high variability of MAO sources (bovine, pig, rat brain or liver, and human) and to the heterogeneity of the experimental protocols used.

A representative prescription for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats

Ethnopharmacological relevanceDing-Zhi-Xiao-Wan (DZ, also known as Kai-Xin-San) is a famous traditional Chinese medicine used for the treatment of emotional disease. Previously, we have found that in a variety of animal models of depression (such as tail suspension model, model of chronic fatigue and forced swimming model) DZ demonstrated significant antidepressant behavior and promoted the production of 5-hydroxytryptamine (5-HT). However, the mechanisms of 5-HT regulation are still unclear. Therefore, the current study is designed to further investigate the antidepressant effect of DZ by observing its influence on 5-HT synthesis, metabolism, transport and other key links, so as to clarify the molecular mechanism of its 5-HT regulation. Materials and methodsSolitary rising combined with the chronic unpredictable mild stress (CMS) was used to establish the rat model of depression. The rats were given DZ for 3 weeks, the behavior change and the following items in hippocampus and prefrontal cortex were detected simultaneously: 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and 5-HT transporter (5-HTT) were observed. ResultsOur results showed that treatment with the DZ significantly improved the behavior and simultaneously increased the 5-HT level in the hippocampus, prefrontal cortex tissues and hippocampus extracellular of depressive rats. In future studies revealed that DZ could significantly increase the protein and mRNA expression of the key enzymes TPH during the 5-HT synthesis process in the hippocampus and prefrontal cortex of the depressed rats, and suppress the expression of 5-HTT protein and mRNA at the same time. But it had no effects on MAO-A and MAO-B activities. ConclusionWe believe that antidepressant effect of DZ is caused by the increase of 5-HT synthesis and reduction of 5-HT re-uptake, and eventually increase the content of 5-HT in the brain and the synaptic gaps.

The antidepressant-like effect of bacopaside I: Possible involvement of the oxidative stress system and the noradrenergic system

In the present study, the antidepressant-like effect of bacopaside I, a saponin compound present in the Bacopa monniera plant, was evaluated by behavioral and neurochemical methods. Bacopaside I (50, 15 and 5mg/kg) was given to mice via oral gavage for 7 successive days. The treatment significantly decreased the immobility time in mouse models of despair tests, but it did not influence locomotor activity. Neurochemical assays suggested that treatment by bacopaside I (50, 15 and 5mg/kg) improved brain antioxidant activity to varying degrees after the behavioral despair test. Bacopaside I (15 and 5mg/kg) significantly reversed reserpine-induced depressive-like behaviors, including low temperature and ptosis. Conversely, bacopaside I did not affect either brain MAO-A or MAO-B activity after the behavioral despair test in mice. Additionally, 5-hydroxytryptophan (a precursor of 5-serotonin) was not involved in the antidepressant-like effect of bacopaside I. These findings indicated that the antidepressant-like effect of bacopaside I might be related to both antioxidant activation and noradrenergic activation, although the exact mechanism remains to be further elucidated.

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B(-/-)) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria.

Antioxidant Activity of Water Extract of Chrysanthemum boreale against MPTP-induced Mice Models

Chrysanthemum boreale(CB) is an oriental medicinal herb which has been used traditionally for the treatment of various brain disease including headache, dizziness and sedation. In order to examine the mechanism of anti-parkinsonism effect, water extract of CB(100 mg and 200 mg/kg of b.w.) were administered orally during 28 days in MPTP-induced parkisonism mice model. Water extract of CB increased the motor activities. CB did not affect total MAO and MAO-B activity in the brain of MPTP-induced mice. CB significantly increased the concentration of lipid peroxidation in the mid brain. Also, CB significantly increased antioxidant enzyme including were SOD, catalase and glutathione peroxidase in the mid brain activity. CB significantly increased the concentration of dopamine and homovanillic acid in the brain. These results suggest that the anti-parkinsonism effect of CB is possibly due to the antioxidative effects at mid brain in MPTP-induced animal model.

Genetic Variants of Neurotransmitter‐Related Genes and miRNAs in Egyptian Autistic Patients

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

Antidepressant-like effect of trans-resveratrol in chronic stress model: Behavioral and neurochemical evidences

Trans-resveratrol is a phenolic compound enriched in polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of trans-resveratrol. The present study investigated whether trans-resveratrol has antidepressant-like activity in rats exposed to chronic stress by using two behavioral tasks, shuttle box and sucrose preference tests. The monoamines (5-HT, noradrenaline and dopamine) and their metabolites as well as monoamine oxidase (MAO) enzyme activities in different brain regions were also measured. Compared to unstressed rats, those exposed to chronic stress paradigm showed performance deficits in the shuttle box, reduced sucrose preference, less weight gain and the increase in the ratio of adrenal gland to body weight, which were reversed by chronic treatment with trans-resveratrol (40 and 80 mg/kg, i.g.). The neurochemical assay showed that higher dose of trans-resveratrol (80 mg/kg) produced a marked increase of 5-HT levels in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased both in the frontal cortex and striatum. Furthermore, chronic treatment with trans-resveratrol was found to inhibit monoamine oxidase-A (MAO-A) activity in all the four brain regions, particularly in the frontal cortex and hippocampus; while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of trans-resveratrol involves the regulation of the central serotonin and noradrenaline levels and the related MAO-A activities.

1,5-Diphenylpenta-2,4-dien-1-ones as potent and selective monoamine oxidase-B inhibitors

A series of (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (3a–r) and (2Z,4E)-3-hydroxy-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-ones (6a–l) were synthesized and evaluated in vitro as inhibitors of the two human Monoamine oxidase (hMAO) isoforms, MAO-A and MAO-B. Most of the compounds showed a selective MAO-B inhibitory activity in the nanomolar or low micromolar range. (2E,4E)-5-(4-Chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)penta-2,4-dien-1-one (3g) and (2E,4E)-5-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)penta-2,4-dien-1-one (3h) were the most potent hMAO-B inhibitors exhibiting IC50 of 4.51 nM and 11.35 nM, respectively, coupled with high selectivity. Moreover, partial recovery of MAO-B activity was observed after repeated washing in the presence of isatin (reversible inhibitor) and compounds 3g and 3h suggesting a reversible inhibition of the enzyme. Molecular mechanics and quantum chemistry methods were used to elucidate the MAO recognition of the most active inhibitors 3g and 3h.

Multitarget-Directed Benzylideneindanone Derivatives: Anti-β-Amyloid (Aβ) Aggregation, Antioxidant, Metal Chelation, and Monoamine Oxidase B (MAO-B) Inhibition Properties against Alzheimer’s Disease

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ(1-42)) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC(50) of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ(1-42) aggregation (80.1%), and MAO-B (IC(50) = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ(1-42) aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.