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Showing papers on "Monoamine oxidase B published in 2015"


Journal ArticleDOI
TL;DR: Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE, and was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B.

129 citations


Journal ArticleDOI
TL;DR: It is demonstrated that cocaine, a Sig-1R agonist, down-regulates the critical enzyme monoamine oxidase B that influences the cocaine-induced dopamine level in a dopamine transporter-independent manner via this never-before-described Sig- 1R-linked genomic action of cocaine.
Abstract: The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

91 citations


Journal ArticleDOI
TL;DR: Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
Abstract: The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.

85 citations


Journal ArticleDOI
TL;DR: It is suggested that compounds other than anthocyanins may be responsible for the observed in vivo MAO inhibition and that the degree of processing and the cultivar of blackcurrant fruit used substantially alter the neuroendocrinological and cognitive benefits conveyed.

69 citations


Journal ArticleDOI
TL;DR: It is demonstrated that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinson's disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders.

63 citations


Journal ArticleDOI
TL;DR: Results suggested that compound 13 might be a promising multifunctional agent for AD treatment.

57 citations


Journal ArticleDOI
01 May 2015-Brain
TL;DR: The preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease.
Abstract: After more than 50 years of treating Parkinson’s disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson’s disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson’s disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson’s disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

52 citations


Journal ArticleDOI
TL;DR: In this article, the combination of a synthetic flavin and alloxan generates a catalyst system which facilitates biomimetic amine oxidation, and electron paramagnetic (EPR) spectroscopic data supports the conclusion that the reaction proceeds through a radical manifold.
Abstract: The flavoenzyme monoamine oxidase (MAO) regulates mammalian behavioral patterns by modulating neurotransmitters such as adrenaline and serotonin. The mechanistic basis which underpins this enzyme is far from agreed upon. Reported herein is that the combination of a synthetic flavin and alloxan generates a catalyst system which facilitates biomimetic amine oxidation. Mechanistic and electron paramagnetic (EPR) spectroscopic data supports the conclusion that the reaction proceeds through a radical manifold. This data provides the first example of a biorelevant synthetic model for monoamine oxidase B activity.

46 citations


Journal ArticleDOI
TL;DR: It is proposed that good substratessuch as BA and PEA might follow the hydride transfer pathway while poor substrates such as NBA prefer the polar nucleophilic mechanism, which might suggest that MAO B can act by both mechanisms.
Abstract: Two of the possible catalytic mechanisms for neurotransmitter oxidative deamination by monoamine oxidase B (MAO B), namely, polar nucleophilic and hydride transfer, were addressed in order to comprehend the nature of their rate-determining step. The Quantum Chemical Cluster Approach was used to obtain transition states of MAO B complexed with phenylethylamine (PEA), benzylamine (BA), and p-nitrobenzylamine (NBA). The choice of these amines relies on their importance to address MAO B catalytic mechanisms so as to help us to answer questions such as why BA is a better substrate than NBA or how para-substitution affects substrate’s reactivity. Transition states were later validated by comparison with the experimental free energy barriers. From a theoretical point of view, and according to the our reported transition states, their calculated barriers and structural and orbital differences obtained by us among these compounds, we propose that good substrates such as BA and PEA might follow the hydride transfer...

37 citations


Journal ArticleDOI
TL;DR: Results showed that the immunoreactive staining and mRNA expression of the dopamine transporter and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra, were significantly increased in mice pretreated with 800 mg/kg of the polysaccharide compared with those in MPTP-treated mice.

30 citations


Journal ArticleDOI
TL;DR: The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds.

Journal ArticleDOI
Elvira Ganic1, Jenny Johansson1, Hedvig Bennet1, Malin Fex1, Isabella Artner1 
TL;DR: It is shown that MaoA and MaoB are expressed in mouse islet β cells and that inhibition of Mao activity reduces insulin secretion in response to metabolic stimuli and that loss of MaoB expression may contribute to the β cell dysfunction in type 2 diabetes.

Journal ArticleDOI
TL;DR: An in-depth computational analysis concerning the role of the enzymatic environment for the reaction mechanism of human MAO-B with different p-substituted benzylamines as substrates shows that steric and electrostatic effects from the active site environment turn the mechanism closer to an asynchronous polar nucleophilic mechanism.
Abstract: The flavin-containing enzyme monoamine oxidase (MAO) is essential for the enzymatic decomposition of amine neurotransmitters. The exact mechanism of the oxidative deamination of amines to aldehydes...

Journal ArticleDOI
TL;DR: 6-substituted 3-arylcoumarins were designed, synthesized and evaluated as cholinesterase (ChE) and monoamino oxidase (MAO) inhibitors to provide neuroprotection against Aβ42-induced cytotoxicity and blood–brain barrier (BBB) penetration capacity (PAMPA-BBB+), and are thus potential anti-Alzheimer agents with balanced activities.
Abstract: Considering the complex etiology of Alzheimer’s disease (AD), multifunctional agents may exhibit important properties against this disease. A series of 6-substituted 3-arylcoumarins (5a–t) were designed, synthesized and evaluated as cholinesterase (ChE) and monoamino oxidase (MAO) inhibitors. Among them, compounds 5o [IC50, 195 nM for human acetylcholinesterase (hAChE), selectivity index, SI (human butyrylcholinesterase, hBuChE/hAChE) = 145; IC50, 63.5 nM for human monoamine oxidase-B (hMAO-B), SI (human monoamine oxidase-A, hMAO-A/hMAO-B) = 25] and 5p [IC50, 185 nM for hAChE, SI (hBuChE/hAChE) = 182; IC50, 196 nM for hMAO-B, SI (hMAO-A/hMAO-B) > 510] were found to selectively inhibit both hAChE and hMAO-B with IC50 values in the nanomolar range. The abilities of 5o and 5p to bind to hAChE and hMAO-B were confirmed by molecular docking and kinetic studies. Moreover, 5o and 5p were found to exhibit significant inhibition of self-induced Aβ42 aggregation (61% and 52%, at 20 μM), have antioxidant properties (0.81 and 1.17 trolox equivalent by ABTS assay), provide neuroprotection against Aβ42-induced cytotoxicity and blood–brain barrier (BBB) penetration capacity (PAMPA-BBB+), and are thus potential anti-Alzheimer agents with balanced activities. Overall, the study provided meaningful information for further development of multifunctional drugs for AD therapy.

Journal ArticleDOI
TL;DR: It is shown that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models, and provides a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA.

Journal ArticleDOI
TL;DR: It is demonstrated that among piperidyl-thienyl chalcones, almost all the compounds exhibit significant MAO-A inhibition, thus may have antidepressant activity, and hence may be applied in the control of senile dementia.
Abstract: A series of piperidyl-thienyl & 2-pyrazoline derivatives of quinolyl-thienyl chalcones were tested to observe the structural characteristics for the monoamine oxidase inhibitory (MAO) activity. In both these series, a diverse range of substituted thiophenes are used which enable the structure activity relationship. The compounds showed enhanced inhibition against MAO-A & B as compared to reference compounds. Compound 1c exhibited most potent MAO-A inhibition having IC50 value of 0.062 M, while 1j showed excellent inhibitory potency against MAO-B having IC50 value of 0.088 M. The present investigation demonstrated that among piperidyl-thienyl chalcones, almost all the compounds exhibit significant MAO-A inhibition, thus may have antidepressant activity. Whereas among the 2-pyrazoline derivatives of chal-cones, many compounds revealed MAOB inhibition and hence may be applied in the control of senile dementia. Molecular docking studies were carried out against human MAO-A and MAO-B to rationalize important binding site interactions.

Journal ArticleDOI
TL;DR: BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO‐B, with additional benefits for comorbid symptoms in PD.
Abstract: Monoamine oxidase B (MAO-B) is well known as a therapeutic target for Parkinson's disease (PD). MAO-B inhibitors retain antiparkinsonism abilities to improve motor function and prevent neuronal loss by decreasing dopamine metabolism and oxidative stress in the brain. From the study to find novel antiparkinsonism drugs that can inhibit MAO-B activity, neuronal loss, and behavioral deficits in the mouse model of PD, we identified that 1-[2-(4-benzyloxyphenoxy)ethyl]imidazole (BPEI) or safinamide strongly and selectively inhibited MAO-B activities in a dose-dependent manner (IC50 of BPEI and safinamide for MAO-B were 0.016 and 0.0021 µM and for MAO-A were 70.0 and 370 µM, respectively). In ex vivo studies after an administration (30 mg/kg, i.p.) of BPEI or safinamide to normal mice, the MAO-B activity in the brain was reduced by up to 90.6% or 82.4% at 1.0 hr. BPEI (20 mg/kg, i.p.) or safinamide (20 mg/kg, i.p.) significantly reversed the behavioral impairments, dopamine levels in the striatum, and neuronal loss in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared with the MPTP-alone-treated group. In the 6-hydroxydopamine-induced PD rat model, behavioral improvement by levodopa sparing activity was observed in the BPEI- or safinamide-treated (20 mg/kg, i.p.) rats. Moreover, BPEI revealed additional curative activities for nonmotor symptoms of PD such as pain, anxiety, epilepsy, and depression in rodent disease models. Therefore, BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO-B, with additional benefits for comorbid symptoms in PD.

Journal ArticleDOI
TL;DR: The results document that the sulfanylphthalimide analogues are selective for the adenosine A1 receptor over the A2A receptor subtype, with a number of compounds also possessing MAO-B inhibitory properties.

Journal ArticleDOI
TL;DR: These data are consistent with studies demonstrating that lower MAO-A activity is associated with elevated serotonin and increased aggression, and low CSF 5HIAA may, in this paradigm, reflect higher serotonin activity.

Journal ArticleDOI
TL;DR: D3-l-DOPA is shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment, and the enhanced behavioral and neurochemical effects produced by D3- l-Dopa and the combination of selegiline/l- DOPA are attributed to decreased metabolism of released dopamine by MAo-B.
Abstract: The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.

Journal ArticleDOI
TL;DR: 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity are investigated as metabolic trapping agents for the monoamine oxidases.
Abstract: The isozymes of monoamine oxidase (MAO-A and MAO-B) are important enzymes involved in the metabolism of numerous biogenic amines, including the neurotransmitters serotonin, dopamine, and norepinephrine. Recently, changes in concentrations of MAO-B have been proposed to be an in vivo marker of neuroinflammation associated with Alzheimer's disease. Previous developments of in vivo radiotracers for imaging changes in MAO enzyme expression or activity have utilized the irreversible propargylamine-based suicide inhibitors or high-affinity reversibly binding inhibitors. As an alternative approach, we have investigated 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines as metabolic trapping agents for the monoamine oxidases. MAO-mediated oxidation and spontaneous hydrolysis yield 1-[(11)C]methyl-2,3-dihydro-4-pyridinone as a hydrophilic metabolite that is trapped within brain tissues. Radiotracers with phenyl, biphenyl, and 7-coumarinyl ethers were evaluated using microPET imaging in rat and primate brains. No isozyme selectivity for radiotracer trapping was observed in the rat brain for any compound, but in the monkey brain, the phenyl ether demonstrated MAO-A selectivity and the coumarinyl ether showed MAO-B selectivity. These are lead compounds for further development of 1-[(11)C]methyl-4-aryloxy-1,2,3,6-tetrahydropyridines with optimized brain pharmacokinetics and isozyme selectivity.

Journal ArticleDOI
TL;DR: The 6-methyl-3-phenylcoumarin scaffold was developed as an agent for multifaceted brain disorders and useful information about the interaction between the enzyme and inhibitor was supplied.
Abstract: A new series of 6-methyl-3-phenylcoumarins (3a–c and 5a–o) and 6-methyl-3-heteroarylcoumarins (5p–s) have been designed, synthesized and evaluated as monoamine oxidase inhibitors. The results demonstrated that a large proportion of the synthesized compounds selectively inhibited monoamine oxidase B with IC50 values in the sub-micromolar range. Among them, compound 5n (IC50 = 0.0601 μM) exhibited the most potent inhibitory activity and the highest selectivity for monoamine oxidase B (SI > 1664-fold). In addition, the possible binding model of the active compound 5n was measured by docking it into the active site of the hMAO-B complex structure. The results showed that compound 5n interacted with the well-known binding pocket of MAO-B, and a π–π interaction was found between the phenyl ring at position 3 of the coumarin and the phenyl ring of Tyr 326. Consequently, we supplied useful information about the interaction between the enzyme and inhibitor, and developed the 6-methyl-3-phenylcoumarin scaffold as an agent for multifaceted brain disorders.

Journal ArticleDOI
TL;DR: In this paper, a human monoamine oxidase B (hMAO B) was used for determination of the total monoamine content in complex matrices by using a glassy carbon paste electrode and adding manganese dioxide microparticles as mediator.
Abstract: We have prepared a biosensor for the determination of the total monoamine content in complex matrices by immobilizing a human monoamine oxidase B (hMAO B) on a glassy carbon paste electrode and adding manganese dioxide microparticles as the mediator. The enzyme hMAO B (expressed in Pichia pastoris and immobilized by using a dialysis membrane) catalyzes the oxidative deamination of monoamines, and this results in the formation of the corresponding aldehyde, ammonia and hydrogen peroxide. The latter was detected at pH 7.5 at a working voltage of 400 mV (vs. Ag/AgCl) by differential pulse voltammetry and amperometrically by applying flow injection analysis. Analytical parameters were established by using phenylethylamine (PEA) as a standard substrate. Peak height and concentration of PEA are linearly related in the 0.5 to 150 μg mL−1 concentration range, and the limits of detection and of quantification are 0.15 and 0.5 μg mL−1 of PEA, respectively. Substrate specificity was investigated with different monoamines including PEA, serotonin, benzylamine, dopamine, tyramine, and norepinephrine. The applicability of the biosensor was successfully tested in a commercial fish sauce that served as a complex matrix. The total monoamine content was calculated as PEA-equivalents.

Journal ArticleDOI
TL;DR: The data indicate that important actions of hormone therapy in the serotonin system may be lost in the context of a HFD, and the interaction of E and diet in surgically menopausal nonhuman primates with a 2×2 block design is examined.
Abstract: The administration of estradiol-17β (E) to animal models after loss of ovarian steroid production has many beneficial effects on neural functions, particularly in the serotonin system in nonhuman primates (NHPs). E also has anorexic effects, although the mechanism of action is not well defined. In the US, obesity has reached epidemic proportions, and blame is partially directed at the Western style diet, which is high in fat and sugar. This study examined the interaction of E and diet in surgically menopausal nonhuman primates with a 2×2 block design. Marmosets (Callithrix jacchus; n=4/group) were placed on control-low fat diet (LFD; 14%kcal from fat) or high fat diet (HFD; 28%kcal from fat) 1month prior to ovariectomy (Ovx). Empty (placebo) or E-filled Silastic capsules were implanted immediately following Ovx surgery. Treatments extended 6months. The established groups were: placebo+LFD, E+LFD, placebo+HFD, or E+HFD. At necropsy, the brain was flushed with saline and harvested. The midbrain was dissected and a small block containing the dorsal raphe nucleus was processed for qRT-PCR using Evagreen (Biotinum). Genes previously found to impact serotonin neural functions were examined. Results were compared with 2-way ANOVA followed by Bonferroni post-hoc tests or Cohen's D analysis. There was a significant effect of treatment on tryptophan hydroxylase 2 (TPH2) across the groups (p=0.019). E stimulated TPH2 expression and HFD prevented E-stimulated TPH2 expression (p<0.01). Treatment differentially affected monoamine oxidase B (MAO-B) across the groups (p=0.05). E increased MAO-B with LFD, and this stimulatory effect was prevented by HFD (p<0.05). There was a significant difference between treatments in corticotrophin releasing factor-receptor 2 (CRF-R2) expression (p=0.012). E increased CRF-R2 and this stimulatory effect was blocked by HFD (p<0.01). Regardless of diet, E increased Fev mRNA (p=0.028) and decreased CRF-receptor 1 (CRF-R1) mRNA (p=0.04). HFD suppressed urocortin 1 (UCN1; stresscopin) expression (p=0.045) but E treatment had no effect. Monoamine oxidase A (MAO-A) was different due to treatment across the groups (p=0.028). MAO-A was increased in the E+HFD group (p<0.01) whereas previous studies showed E suppressed MAO-A in macaques. The serotonin reuptake transporter (SERT), the serotonin 1A receptor (5HT1A), estrogen receptor beta (ERβ) and progestin receptor (PR) expressions were not different between groups. Estrogen receptor alpha (ERα) was undetectable. In summary, the data indicate that important actions of hormone therapy in the serotonin system may be lost in the context of a HFD.

Journal ArticleDOI
TL;DR: It may be concluded that the acetophenone derivatives could be used to develop promising lead compounds for treating neurodegenerative diseases.
Abstract: Two series of acetophenone derivatives have been designed, synthesized and evaluated for human monoamine oxidase A and B inhibitory activity in vitro. Most of the tested compounds acted preferentially on MAO-B with IC50 values in the nanomolar range and weak or no inhibition of MAO-A. In particular, compounds 1j (IC50 = 12.9 nM) and 2e (IC50 = 11.7 nM) were the most potent MAO-B inhibitors being 2.76- and 2.99-fold more active than selegiline. In addition, the structure–activity relationships for MAO-B inhibition indicated that substituents at C3 and C4 of the acetophenone moiety, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking and kinetic studies have been carried out to explain the binding modes of MAO-B with the acetophenone derivatives. Furthermore, the representative compounds 1j and 2e showed low neurotoxicity in SH-SY5Y cells. It may be concluded that the acetophenone derivatives could be used to develop promising lead compounds for treating neurodegenerative diseases.

Journal ArticleDOI
TL;DR: A fluorescence-based enzymatic assay that can quantify isatin in blood samples is developed and provided a straightforward method for further investigation of isatin as a biomarker in human health.
Abstract: Isatin is an endogenous inhibitor of monoamine oxidase B and is found in human blood and tissue. Increased levels of isatin have been linked to stress and anxiety in rodents and humans; however, th...

Journal ArticleDOI
TL;DR: Variation in monoamine oxidase activity seems to reflect the compensatory mechanisms triggered in degrading nigrostriatal dopaminergic system.
Abstract: Activities of monoamine oxidases A and B were examined on the models of presymptomatic and early symptomatic stages of Parkinson's disease developed in mice treated with MPTP, a specific neurotoxin affecting dopaminergic neurons. Activity of monoamine oxidases A, the key enzyme of dopamine degradation, is increased in neuronal somas during the symptomatic stage, and it is augmented in the axons during both stages. Neuronal activity of monoamine oxidases A is higher during the symptomatic stage than that during the presymptomatic stage, which can explain depletion of intercellular dopamine and appearance of motor disturbances. Activity of monoamine oxidase B in the striatum is reduced during the presymptomatic stage, but returns to the control level during the symptomatic stage. Variation in monoamine oxidase activity seems to reflect the compensatory mechanisms triggered in degrading nigrostriatal dopaminergic system.

Journal ArticleDOI
TL;DR: MAO-B inhibitors are effectively used for the symptomatic treatment of Parkinson's disease and in the early stages of this disease, these drugs are safe and very well tolerated.
Abstract: MAO-B inhibitors are effectively used for the symptomatic treatment of Parkinson's disease (PD). In the early stages of this disease, these drugs are safe and very well tolerated. However their eff...

Journal ArticleDOI
Qiang Chen1, Yang Xu1, Hui Zhang1, Xiao Tan1, Shu Hui Liu1, Fen Yan 
TL;DR: Immunohistochemistry is used to investigate subcellular localization of monoamine oxidase type B (MAOB) in the axon of the rat's peripheral nervous system and may be closely associated with both axonal transport and nerve conduction.
Abstract: Immunohistochemistry is used to investigate subcellular localization of monoamine oxidase type B (MAOB) in the axon of the rat's peripheral nervous system. Through light and electron microscopy, the presence of MAOB-immunoreactive structures in the propria lamina of tongue and on the outer membranes of mitochondria in both myelinated and unmyelinated axons can be detected. As a result, MAOB may potentially play a crucial role in the axons of the rat's peripheral nervous system and may be closely associated with both axonal transport and nerve conduction.

Journal ArticleDOI
26 Mar 2015
TL;DR: Savinamide is a putative, important drug for the therapy of Parkinson's disease with an efficacy superior to available irreversible monoamine oxidase B inhibitors or N-methyl-D-aspartate receptor antagonists.
Abstract: The main feature of Parkinson's disease is slowly ongoing neuronal death. Changes of neurotransmission of biogenic amines, such as dopamine, cause the heterogeneity of motor and non-motor symptoms. Therefore, compounds with a broad spectrum of mechanisms of action are ideal candidates for the treatment of the disease. Safinamide reduces dopamine turnover by reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, and modulation of calcium channels and of glutamate release. Safinamide requires one-time daily intake within a dose range of 50 and 100 mg. Clinical trials demonstrated that safinamide is well tolerated and safe and ameliorates motor behavior when combined with dopamine agonist only or dopamine agonist and levodopa. Safinamide is a putative, important drug for the therapy of Parkinson's disease with an efficacy superior to available irreversible monoamine oxidase B inhibitors or N-methyl-D-aspartate receptor antagonists.