Effects Of Monoamine Oxidase Inhibitors Research Articles

Investigating Serotonin Dynamics and Simulating Effects of Antidepressants Using Variation in Enzyme Expression

Serotonin plays a crucial role in the symptoms of depression, and understanding its dynamics in the brain is of the utmost importance in determining how to mitigate the effects of depression. We investigate a mathematical model presented by Best et al. (2020) that examines serotonin dynamics in the substantia nigra pars reticulata. By incorporating experimental data and a stochastic systems population model, several biological mechanisms and observations are further understood. A populations model is utilized to account for enzymatic expression level variation from 75% to 125% of their base values. When generating the population model, uniform distributions are assumed when simulating maximum velocity values, which correspond to enzyme expression levels. We investigate this assumption and show that it is reasonably insensitive; that is, changes in the distributions used to generate these values do not significantly change the results of the model. We also use the model to simulate the effects of monoamine oxidase inhibitors (MAOIs), one of the first treatments discovered for depression. We then use similar methods to simulate the effects of selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant used today. We demonstrate that low enzyme expression levels of tryptophan hydroxylase and neutral amino acid transporter are most associated with low extracellular serotonin values at the steady state, indicating that these two enzymes may play key roles in predicting which patients may or may not respond to SSRI treatment.

Inhibition of monoamine oxidase B reduces atherosclerosis and fatty liver in mice.

Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In the present study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was up-regulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD.

Molecular Investigation of the Antitumor Effects of Monoamine Oxidase Inhibitors in Breast Cancer Cells.

The catalytic activity of monoamine oxidase A (MAO-A) has been linked to tumorigenesis due to the production of reactive oxygen species (ROS) and the resulting oxidative stress. MAO-A inhibition revealed a beneficial role in prostate and lung cancer treatment. This study is aimed at evaluating the effect of different monoamine oxidase A inhibitors (MAO-AIs) on the proliferation and progression of breast cancer cell lines. The cell viability assay was used to evaluate the antiproliferative and combined effects of MAO-AIs. Cell migration was evaluated using wound healing, invasion, and colony formation assays. The underlying mechanism of cell death was studied using flow cytometry. The real-time polymerase chain reaction was used to determine the relative gene expression. Finally, MAO-A activity in breast cancer cells was evaluated using an MAO-A activity assay. According to the results, the examined MAO-AIs significantly inhibited the proliferation of breast cancer cells in a dose-dependent manner. In breast cancer cells, the combination of anticancer drugs (doxorubicin or raloxifene) with MAO-AIs resulted in a synergistic effect. MAO-AIs significantly reduced wound closure and invasion ability in breast cancer cells. Also, MAO-AIs reduced the colony count and size of breast cancer cells. MAO-AIs resulted in significant proapoptotic activity in breast cancer cells. Finally, the MAO-AIs suppressed MAO-A, Bcl-2, and VEGF gene expressions in breast cancer cells relative to untreated cells. This study provides solid evidence supporting the anticancer effect of MAO-A inhibitors in breast cancer cells.

Risk of serotonin syndrome in acutely ill patients receiving linezolid and opioids concomitantly: a retrospective cohort study

IntroductionLinezolid is an oxazolidinone antibiotic with a reversible, non-selective, monoamine oxidase inhibitory effect. Combining linezolid with serotonergic agents may increase serotonin syndrome (SS) risk.Linezolid is recommended in patients with suspected or confirmed resistant Gram-positive bacterial infections, especially if vancomycin cannot be used. However, it is unclear whether co-administration of linezolid with opioids increases the risk of serotonin syndrome. Research objectiveTo establish whether combining linezolid with opioids will increase the incidence of SS in acutely ill patients. MethodsThis was a retrospective observational study. All adult patients who were admitted and received linezolid between March and September 2020 were included in the study. The primary outcome was the prevalence of SS, as defined by Hunter's criteria. ResultsThe study included 106 patients, most whom were males (91.5%). More than half of the cohort (56.6%) received a concomitant opioid agent. Morphine and fentanyl were the most prescribed opioids (37.7% and 34%, respectively). Among patients who received opioids, only one patient (1.6%) had spontaneous clonus. However, this patient developed spontaneous clonus post cardiac arrest, which made an association with the linezolid–opioids combination less likely. ConclusionIn this study, the incidence of SS was low in acutely ill patients who received concomitant linezolid and opioids. However, larger prospective studies are required to confirm this finding.

Repurposing monoamine oxidase inhibitors (MAOI) for the treatment of rheumatoid arthritis possibly through modulating reactive oxidative stress mediated inflammatory cytokines.

Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H2O2) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA.

Stephtetrandrine A-D, bisbenzylisoquinoline alkaloids from Stephania tetrandra

Four undescribed bisbenzylisoquinoline alkaloids, designated as Stephtetrandrine A-D, were isolated from the roots of Stephania tetrandra. Their structures were elucidated by IR, HRESIMS, ECD spectra, 1 D and 2 D NMR spectra and comparison with the literature data. Additional five known compounds (limacine, tetrandrine, N-trans-Feruloyltyramine, 2′-N-chloromethyltetrandrine, 2,2'-N-N-dichloromethyltetrandrine) were also isolated. N-trans-Feruloyltyramine was isolated from Stephania tetrandra for the first time. The isolated compounds were tested for monoamine oxidase, acetylcholinesterase, phosphoinositide 3-kinase α and human hepatoma cell HepG2 inhibitory activities. Stephtetrandrine C showed obvious inhibitory effect on human hepatoma HepG2, with IC50 value of 16.2 μM. Limacine and 2′-N-chloromethyltetrandrine showed moderate monoamine oxidase inhibitory effect with the IC50 values of 37.7 and 29.2 μM, respectively.

Trace Amine-Associated Receptor 1 Regulates Central Effects of Monoamine Oxidase Inhibitors: Involvement of Tyramine and Glutamate

SEE CORRESPONDING ARTICLE ON PAGE 16 TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase InhibitionBiological PsychiatryVol. 90Issue 1PreviewMonoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. Full-Text PDF Open Access

Monoamine Oxidase Inhibitory Effects of Medicinal Plants in Management of Alzheimer's Disease

Alzheimer's disease is the most common progressive neurodegenerative disorder that effects large population of society especially elderly people. Environmental and/or genetic factors contribute Alzheimer's disease to become a pivotal health problem but this relationship remains ambiguous. Globally growing prevalence of Alzheimer’s disease requires to understand cellular pathways that lead to Alzheimer’s disease and to develop new strategies for prevention and treatment. Elevated monoamine oxidase (MAO) enzymes activity with ages is associated with etiology of Alzheimer's disease. Inhibition of monoamine oxidase enzyme can protect from neuronal damage, thus it become one of the key pathway for management of Alzheimer’s disease. Using bioactive compounds from medicinal plants as potential monoamine oxidase inhibitors might be a better solution considering undesired side effects of synthetic drugs on human body. The purpose of this review is to implicate the importance of pharmacophore analysis which explains pharmacological properties of medicinal plants and interaction of bioactive compound from plants with MAO enzyme.

Comparative effects of berberine and piperine on the neuroprotective potential of neostigmine

This study examined effect of berberine and piperine on neuroprotective potential of neostigmine in the management of neurological disorders. Berberine and neostigmine were weighed (30g), dissolved in distilled water (30mL) separately, while, 30mg piperine was dissolved in ethanol (0.45mL), made up to 30mL with distilled water. Antioxidant activities in 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH), 2, 2-azinobis (3-ethylbenzothiazoline-6-sulfonate) radical (ABTS), Fe-chelation, ferric reducing properties (FRAP), nitric oxide (NO) and hydroxyl (OH) radical scavenging abilities and Fe2+, cisplatin and sodium nitroprusside (SNP) induced lipid peroxidation (LPO), and acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activities were assessed in vitro. The result revealed that tested compounds inhibited enzymes activities dose-dependently. However, berberine (IC50=0.17mg/mL) had slight higher AChE inhibitory effect than piperine and neostigmine (p<0.05). Also, berberine had the highest BChE inhibitory effect (IC50=0.16mg/mL) while piperine exhibited the highest MAO inhibitory effect (IC50=0.21mg/mL). Berberine, piperine and neostigmine exhibited high antioxidant properties and inhibited Fe2+, cisplatin and SNP induced LPO. Both alkaloids demonstrated antiradical scavenging ability comparable to neostigmine action against Alzheimer's disease (AD). The modulatory and antioxidant berberine and piperine properties on these enzymes (AChE, BChE and MAO) could be possible underlying mechanisms in employing these compounds as a complementary therapy in neurodegenerative diseases (NDDs) management.

Study of monoamine oxidase inhibitory effects of seven Iranian medicinal plant extracts

Study of monoamine oxidase inhibitory effects of seven Iranian medicinal plant extracts

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

BackgroundMonoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. MethodsBehavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. ResultsBoth antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild-type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. ConclusionsThese observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.

Solanum leaves extracts exhibit antioxidant properties and inhibit monoamine oxidase and acetylcholinesterase activities (in vitro) in Drosophila melanogaster.

Background This study sought to determine the in vitro antioxidant, anti-monoamine oxidase and anticholinesterase properties of extracts (aqueous and alkaloid) of two tropical vegetables from Solanum spp- African eggplant (Solanum macrocarpon L) and black nightshade (Solanum nigrum L) as indices of their neuroprotective properties. Methods Both aqueous and alkaloid extracts of African eggplant (AE) and black nightshade (BN) were prepared by solvent extraction according to standard methods. Thereafter, the inhibitory effects of the extracts on monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities, as well as their free radical-scavenging and reducing abilities were assessed. Also, phytochemical analysis for phenols, flavonoids, and alkaloids were carried out. Results The results showed that the extracts inhibited MAO and AChE activities dose dependently, with aqueous extracts showing significantly higher MAO inhibition that the alkaloid extracts from both samples, but in all, BN showed higher MAO inhibitory effect compared to AE; the reverse was however, observed for AChE inhibition. Furthermore, the aqueous extracts showed significantly higher antioxidant properties than the alkaloid extracts, while BN had higher antioxidant properties compared to AN. The phytochemical analysis also showed that BN had significantly higher amount of phenols, flavonoids, and alkaloids than AE. Conclusions The anti-monoamine oxidase, anticholinesterase, and antioxidant properties exhibited by extracts from both samples could contribute to their neuroprotective abilities. Thus, these vegetables can be potential sources of functional foods and nutraceuticals in the management of neurodegenerative diseases, especially in the tropics.

In vitro anticholinesterase, antimonoamine oxidase and antioxidant properties of alkaloid extracts from kola nuts (Cola acuminata and Cola nitida).

Background The development of cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for management of neurodegenerative diseases such as Alzheimer's disease (AD) has come with their undesirable side effects. Hence, research for potent but natural ChE and MAO inhibitors with little or no side effects is essential. This study investigated the potentials of alkaloid extracts from two Cola species as nutraceuticals for prevention and management of AD. Methods Alkaloid extracts were obtained from two Cola species (Cola nitida [KN] and Cola acuminata [KA]) by solvent extraction method. The extracts were characterized for their alkaloid contents using gas chromatography (GC). The effects of the extracts on ChE and MAO activities were investigated in vitro. Also, the extracts' ability to inhibit Fe2+-induced lipid peroxidation in rat brain homogenate, scavenge DPPH and OH radicals, as well as chelate Fe2+ were determined. Results GC characterization revealed the presence of augustamine and undulatine as the predominant alkaloids in the extracts. There was no significant (P > 0.05) difference in the inhibitory effects of the extracts on ChE activities. However, KA extract exhibited significantly higher (P < 0.05) MAO inhibitory effect than KN. Also, KA extract inhibited Fe2+- induced malondialdehyde (MDA) production in rat brain homogenate more significantly than KN, while there was no significant difference in DPPH and OH radicals scavenging, as well as Fe2+-chelating abilities of the extracts. Conclusions Our findings revealed that KN and KA alkaloid extracts exhibited significant effect in vitro on biological pathways that may contribute to neuroprotection for the management of neurodegenerative diseases.

Effect of monoamine oxidase inhibitors on ischaemia/reperfusion-induced acute kidney injury in rats

Increases in renal sympathetic nerve activity during ischaemia and renal venous norepinephrine levels after reperfusion play important roles in the development of ischaemia/reperfusion-induced acute kidney injury. In the present study, we examined the effect of isatin, an endogenous monoamine oxidase inhibitor, on renal venous norepinephrine levels, superoxide production after reperfusion, and ischaemia/reperfusion-induced acute kidney injury. Ischaemia/reperfusion-induced acute kidney injury was accomplished by clamping the left renal artery and vein for 45min, followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal superoxide production and norepinephrine overflow were elevated and significant renal tissue damage was observed following ischaemia/reperfusion injury. Intravenous injection of isatin (10mg/kg) at 5min before ischaemia increased the renal venous plasma norepinephrine level after reperfusion and aggravated ischaemia/reperfusion-induced renal dysfunction and histological damage. The excessive superoxide production after reperfusion was significantly suppressed by isatin administration, indicating that the inhibition of oxidative deamination effectively suppressed superoxide production. These data suggest that the exacerbation effect of isatin is associated, at least in part, with increased norepinephrine levels but not with superoxide production. To the best of our knowledge, this is the first report of isatin involvement in the pathogenesis and/or development of acute kidney injury.

Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.

Phenolic Extracts from Clerodendrum volubile Leaves Inhibit Cholinergic and Monoaminergic Enzymes Relevant to the Management of Some Neurodegenerative Diseases

ABSTRACTThis study investigated the inhibitory effects of phenolic-rich extracts from Clerodendrum volubile leaves on cholinergic [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoaminergic [monoamine oxidase (MAO)] enzymes' activities and pro-oxidants [Fe2+ and quinolinic acid-(QA)] induced lipid peroxidation in rats brain homogenates in vitro. Free phenolic extracts (FPE) and bound phenolic extracts (BPE) were obtained via solvent extraction, and the total phenol and flavonoid contents were evaluated. The phenolic constituents of the extracts were also determined using high performance liquid chromatography coupled with diode array detector (HPLC-DAD). Our findings revealed that FPE had higher AChE (2.06 μg/mL), BChE (2.79 μg/mL), and MAO (2.81 μg/mL) inhibitory effects than BPE [AChE, 2.80 μg/mL; BChE, 3.40 μg/mL; MAO, 3.39 μg/mL]. Furthermore, FPE also had significantly (P < 0.05) higher inhibitory effects on Fe2+ and QA-induced lipid peroxidation compared to BPE. FPE (162.61 mg GAE/g) had higher total phenol content than BPE. However, BPE (18.65 mg QE/g) had significantly higher total flavonoid content than FPE (13.32 mg QE/g). Phenolic acids (such as gallic acid, catechin, chlorogenic, caffeic, ellagic, p-Coumaric acids) and flavonoids (catechins, rutin and quercetin) were present in both extracts. This study revealed that the enzymes' inhibitory activities and antioxidant potentials of phenolic-rich extracts from C. volubile could be part of the mechanism of actions behind its use for memory/cognitive function as obtained in folklore. However, FPE exhibited significantly higher enzymes, inhibitory and antioxidant potentials than BPE.

Cudraticusxanthone A isolated from the roots of Cudrania tricuspidata inhibits metastasis and induces apoptosis in breast cancer cells

Ethnopharmacological relevanceThe roots of Cudrania tricuspidata is a deciduous tree found in Korea, China, and Japan. C. tricuspidata contains an abundance of various minerals, B vitamins, and flavonoids to help prevent diverse cancers. Cudratricusxanthone A (CTXA), a compound isolated from the roots of C. tricuspidata, has potent anti-proliferative, antioxidative, and monoamine oxidase inhibitory effects. Aim of the studyIn the present study, cudratricusxanthone A (CTXA) is a xanthone isolated from the bioassay-guided fractionation of the EtOH extract of C. tricuspidata with strong anti-cancer activity in breast cancer cells. The effect of CTXA on cell migration and apoptosis were evaluated in the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. Materials and methodsEffects of CTXA on phorbol 12-myristate 13-acetate (PMA)-induced MCF-7 and MDA-MB-231 cells. Flow cytometric measurements of CTXA-induced apoptosis in breast cancer cells. ResultsThe results show that CTXA gradually reduced viability of the two breast cancer cell lines and induced apoptosis in a concentration-dependent manner. Moreover, CTXA effectively blocked breast cancer cell migration and invasion. CTXA decreased the expression of matrix metalloproteinase-9, extracellular regulated kinases 1 and 2 and phosphorylation of the inhibitor IκBα in the MCF-7 and MDA-MB-231 cell lines. ConclusionsCollectively, these results indicate that CTXA possesses anti-cancer activities and provide a basis for developing effective therapeutic agents to inhibit growth and metastasis of breast cancer.

Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer’s disease

Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the “N-methyl” position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD.

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine.

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately-reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self-administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking.

The separate and combined effects of monoamine oxidase A inhibition and nicotine on resting state EEG.

While nicotine is often associated with the neuropsychological effects of tobacco smoke, the robust monoamine oxidase (MAO) inhibition observed in chronic smokers is also likely to play a role. Electroencephalographically-indexed alterations in baseline neural oscillations by nicotine have previously been reported in both smokers and non-smokers, however, little is known about the effects of MAO inhibition in combination with nicotine on resting state EEG. In a sample of 24 healthy non-smoking males, the effects of 6 mg nicotine gum, as well as MAO-A inhibition via 75 mg moclobemide, were investigated in separate and combined conditions over four separate test sessions. Drug effects were observed in the alpha2, beta2, and theta band frequencies. Nicotine increased alpha2 power, and moclobemide decreased beta2 power. Theta power was decreased most robustly by the combination of both drugs. Therefore, this study demonstrated that the nicotinic and MAO inhibiting properties of tobacco may differentially influence fast-wave oscillations (alpha2 and beta2), while acting in synergy to influence theta oscillations.