Monoamine Oxidase A Levels Research Articles

A Relationship of Monoamine Oxidase-A with Serotonin in Violent Antisocial Behavior in Iraqi Prisoners

It is thought that the monoamine oxidase-A (MAOA) enzyme, which catalyzes key brain signaling chemicals like serotonin, noradrenaline, and dopamine, indirectly influences antisocial behavior by disrupting the neurotransmitter balance in brain regions and neural networks. This study aims to assess the MAOA enzyme level in serum and serotonin linked to antisocial behavior in cases in the prison of Baghdad City, Iraq. Blood samples were collected from (63) prisoners and (27) control groups, ages 18 years to 65 years, with a mean ± SD of 37.8 ± 8.8, all males, with different prison terms and different crimes for prisoners in the prison at Baghdad City, Iraq. MAOA and serotonin levels were measured in serum in prisoners and healthy men, and the results showed the serum levels of MAOA enzyme and serotonin were decreased in prisoners compared to the healthy (11.5 IU/ml vs. 19.5 IU/ml) and (79 IU/ml vs. 439 IU/ml), respectively, with the observed difference being significant (P < 0.001(. The results of the relationship between education and social violence were: illiterate 11.1%, primary school 27%, secondary 52.4%, and university 9.5%. The median serum level of MAOA and serotonin in the age group 18–39 years was (11.3 IU/ml, 68.3 ng/ml), respectively, and in the age group 40–65 years was (13 IU/ml, 139 ng/ml), respectively.

Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer's Disease Brain.

Increased monoamine oxidase-A (MAO-A) activity in Alzheimer's disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [18F]FAZIN3 for MAO-A, [18F]flotaza and [125I]IBETA for Aβ plaques, [124/125I]IPPI for tau, and [18F]FEPPA for TSPO imaging. Brain sections of the anterior cingulate (AC; gray matter GM) and corpus callosum (CC; white matter WM) from cognitively normal control (CN, n = 6) and AD (n = 6) subjects were imaged using autoradiography and immunostaining. Using competition with clorgyline and (R)-deprenyl, the binding of [18F]FAZIN3 was confirmed to be selective to MAO-A levels in the AD brain sections. Increases in MAO-A, Aβ plaque, tau, and TSPO activity were found in the AD brains compared to the control brains. The [18F]FAZIN3 ratio in AD GM versus CN GM was 2.80, suggesting a 180% increase in MAO-A activity. Using GM-to-WM ratios of AD versus CN, a >50% increase in MAO-A activity was observed (AD/CN = 1.58). Linear positive correlations of [18F]FAZIN3 with [18F]flotaza, [125I]IBETA, and [125I]IPPI were measured and suggested an increase in MAO-A activity with increases in Aβ plaques and tau activity. Our results support the finding that MAO-A activity is elevated in the anterior cingulate cortex in AD and thus may provide a new biomarker for AD in this brain region.

Antidepressant effects of p-coumaric acid isolated from Vaccinium bracteatum leaves extract on chronic restraint stress mouse model and antagonism of serotonin 6 receptor in vitro

BackgroundVaccinium bracteatum Thunb. leaves (VBL) are used in traditional herbal medicines to treat various biological diseases. p-coumaric acid (CA), the main active component of VBL, has neuroprotective effects against corticosterone-induced damage in vitro. However, the effects of CA on immobility induced by chronic restraint stress (CRS) in a mouse model and 5-HT receptor activity have not been investigated. Hypothesis/PurposeWe investigated the antagonistic effects of VBL, NET-D1602, and the three components of Gαs protein-coupled 5-HT receptors. Additionally, we identified the effects and mechanism of action of CA, the active component of NET-D1602, in the CRS-exposed model. MethodsFor in vitro analyses, we used 1321N1 cells stably expressing human 5-HT6 receptors and CHO-K1 expressing human 5-HT4 or 5-HT7 receptors cell lines to study the mechanism of action. For in vivo analyses, CRS-exposed mice were orally administered CA (10, 50, or 100 mg/kg) daily for 21 consecutive days. The effects of CA were analyzed by assessing behavioral changes using a forced swim test (FST), measuring levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones in ntial therapeutic effects as 5-HT6 receptor antagonists for neurodegenerative diseases and depressioserum, and acetylcholinesterase (AChE), monoamines, including 5-HT, dopamine, and norepinephrine, using enzyme-linked immunosorbent assay kits. The underlying molecular mechanisms of the serotonin transporter (SERT), monoamine oxidase A (MAO-A), and extracellular signal-regulated kinase (ERK)/protein kinase B (Akt)/mTORC1 signaling were detected using western blotting. ResultsCA was confirmed to be an active component in the antagonistic effects of NET-D1602 on 5-HT6 receptor activity through decreases in cAMP and ERK1/2 phosphorylation. Moreover, CRS-exposed mice treated with CA showed a significantly reduced immobility time in the FST. CA also significantly decreased corticosterone, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) levels. CA enhanced 5-HT, dopamine, and norepinephrine levels in the hippocampus (HC) and prefrontal cortex (PFC) but decreased MAO-A and SERT protein levels. Similarly, CA significantly upregulated the ERK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt/mTOR/p70S6K/S6 signaling pathways in both HC and the PFC. ConclusionCA contained in NET-D1602 may play the antidepressant effects against CRS-induced depression-like mechanism and the selective antagonist effect of 5-HT6 receptor.

Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.

Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood. Here, the influence of MAOA promoter/exon I/intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females). No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr = .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT. In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5' on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system. NCT02582398 (https://clinicaltrials.gov/ct2/show/NCT02582398).

Ginkgolide-Platinum(II) Complex GPt(II) Exhibits Therapeutic Effect on Depression in Mice via Upregulation of DA and 5-HT Neurotransmitters.

BackgroundDepression is the 5th most prevalent disorder adversely affecting the health of humans worldwide. The present study evaluated the antidepressant effect of ginkgolide-platinum(II) complex in vivo in a mice model of CMS-induced depression.Material/MethodsDepression was induced in mice by social isolation followed by chronic mild stress. After stress, the mice were assigned randomly to a model group, a 3 mg/kg group, a 6 mg/kg group, and a 12 mg/kg group. The mice in the 3 treatment groups were intraperitoneally injected with a single dose of 3.0, 6.0, or 12.0 mg/kg GPt(II) on day 11 of stress. The behavioral changes in mice were analyzed on day 21 of GPt(II) treatment by suspension and open field tests.ResultsThe GPt(II) treatment significantly increased the numbers of crossings and rearings in CMS mice. Treatment of mice with GPt(II) significantly elevated dopamine, BDNF, and serotonin levels in hippocampus tissues. The CMS-mediated reduction of neuropeptide production in the hippocampus tissues was significantly alleviated by GPt(II) treatment (P<0.05). The GPt(II) treatment suppressed the effect on CMS-induced elevated level of MAO-A in hippocampus tissues. Treatment with GPt(II) significantly repressed caspase-3 activation induced by CMS in the hippocampus tissues of mice. The GPt(II) treatment significantly (P<0.05) upregulated Hsp70 mRNA level in depression model mice. The levels of dopamine, serotonin, and BDNF were increased from 187.83±8.53, 289.65±10.76, and 7.98±1.87 ng/g, respectively, in the model group to 657.63±24.47, 720.54±28.09, and 22.56±3.11 ng/g, respectively, in the 12 mg/kg GPt(II) treatment group.ConclusionsGPt(II) treatment significantly relieved characteristics of depression in the mice through upregulation of neurotransmitter, neuropeptide, and Hsp70 expression. Moreover, GPt(II) downregulated monoamine oxidase-A levels in the mouse hippocampus tissues. Therefore, further research is warranted on the possible therapeutic effect of GPt(II) in the treatment of depression.

The effect of electroconvulsive therapy on cerebral monoamine oxidase A expression in treatment-resistant depression investigated using positron emission tomography

BackgroundElectroconvulsive therapy (ECT) constitutes one of the most effective antidepressant treatment strategies in major depression (MDD). Despite its common use and uncontested efficacy, its mechanism of action is still insufficiently understood. Previously, we showed that ECT is accompanied by a global decrease of serotonin-1A receptors in MDD; however, further studies to investigate the involvement of the serotonergic system in the mechanism of action of ECT are warranted. The monoamine oxidase A (MAO-A) represents an important target for antidepressant treatments and was found to be increased in MDD. Here, we investigated whether ECT impacts on MAO-A levels in treatment-resistant patients (TRD). Methods16 TRD patients (12 female, age 45.94 ± 9.68 years, HAMD 25.12 ± 3.16) with unipolar depression according to DSM-IV were scanned twice before (PET1 and PET2, to assess test-retest variability under constant psychopharmacotherapy) and once after (PET3) completing a minimum of eight unilateral ECT sessions using positron emission tomography and the radioligand [11C]harmine to assess cerebral MAO-A distribution volumes (VT). Age- and sex-matched healthy subjects (HC) were measured once. ResultsResponse rate to ECT was 87.5%. MAO-A VT was found to be significantly reduced after ECT in TRD patients (−3.8%) when assessed in 27 a priori defined ROIs (p < 0.001). Test-retest variability between PET1 and PET2 was 3.1%. MAO-A VT did not significantly differ between TRD patients and HC at baseline. ConclusionsThe small effect size of the significant reduction of MAO-A VT after ECT in the range of test-retest variability does not support the hypothesis of a clinically relevant mechanism of action of ECT based on MAO-A. Furthermore, in contrast to studies reporting elevated MAO-A VT in unmedicated depressed patients, MAO-A levels were found to be similar in TRD patients and HC which might be attributed to the continuous antidepressant pharmacotherapy in the present sample.

Depressed mood induction in early cigarette withdrawal is unaffected by acute monoamine precursor supplementation.

BackgroundCigarette smoking is the leading preventable cause of death; however, quitting is difficult and early relapse is common. Dysphoric mood during early cigarette withdrawal is associated with relapse, and with the exception of bupropion and nortriptyline, few interventions have been developed to prevent this. During early cigarette withdrawal there is an elevation in the levels of monoamine oxidase-A (MAO-A), which removes monoamines excessively and induces oxidative stress and is implicated in creating sad mood. Hence, we conducted a randomized, placebo-controlled, double-blind crossover trial of a dietary supplement designed to counter the effects of elevated MAO-A levels on vulnerability to depressed mood.MethodsTwenty-one otherwise healthy cigarette smokers completed the protocol, receiving either active dietary supplement followed by washout and placebo or the same in reverse order. The dietary supplement was composed of monoamine precursors (2 g tryptophan, 10 g tyrosine) and blueberry antioxidants (blueberry juice with blueberry extract). Vulnerability to depressed mood was measured by the change in scores of depressed mood on the visual analog scale (VAS) following the sad mood induction paradigm (MIP).ResultsThere was a significant increase in VAS depressed mood scores after the sad MIP during supplement and placebo, but no difference between active and placebo conditions. There was also a significant increase in urge-to-smoke scores after sad MIP during supplement and placebo but no difference between active and placebo conditions. Reliability of the increase in VAS after MIP was very good.ConclusionThe dietary supplement had negligible effect on depressed mood, but sad MIP is a very reliable method that can be applied in future studies to assess other interventions for preventing dysphoric mood during early cigarette withdrawal.

Brain monoamine oxidase A in seasonal affective disorder and treatment with bright light therapy

Increased cerebral monoamine oxidase A (MAO-A) levels have been shown in non-seasonal depression using positron emission tomography (PET). Seasonal affective disorder (SAD) is a sub-form of major depressive disorder and is typically treated with bright light therapy (BLT). The serotonergic system is affected by season and light. Hence, this study aims to assess the relevance of brain MAO-A levels to the pathophysiology and treatment of SAD. Changes to cerebral MAO-A distribution (1) in SAD in comparison to healthy controls (HC), (2) after treatment with BLT and (3) between the seasons, were investigated in 24 patients with SAD and 27 HC using [11C]harmine PET. PET scans were performed in fall/winter before and after 3 weeks of placebo-controlled BLT, as well as in spring/summer. Cerebral MAO-A distribution volume (VT, an index of MAO-A density) did not differ between patients and HC at any of the three time-points. However, MAO-A VT decreased from fall/winter to spring/summer in the HC group (F1, 187.84 = 4.79, p < 0.050), while SAD showed no change. In addition, BLT, but not placebo, resulted in a significant reduction in MAO-A VT (F1, 208.92 = 25.96, p < 0.001). This is the first study to demonstrate an influence of BLT on human cerebral MAO-A levels in vivo. Furthermore, we show that SAD may lack seasonal dynamics in brain MAO-A levels. The lack of a cross-sectional difference between patients and HC, in contrast to studies in non-seasonal depression, may be due to the milder symptoms typically shown by patients with SAD.

Elevated monoamine oxidase A activity and protein levels in rodent brain during acute withdrawal after chronic intermittent ethanol vapor exposure

BackgroundA key component of alcohol dependence (AD), a severe form of alcohol use disorder, is the negative emotional state during withdrawal. Monoamine oxidase A (MAO-A) is an important enzyme that metabolizes monoamines and creates oxidative stress. Elevations in MAO-A level, especially in the prefrontal and anterior cingulate cortex (PFC and ACC), are associated with low mood states, including the dysphoria of early alcohol withdrawal in humans. The aim of the present study was to determine whether chronic alcohol vapor exposure causes an upregulation of MAO-A activity or level in the PFC and ACC of rodents during acute withdrawal. MethodsSprague-Dawley rats were exposed to ethanol vapor or control condition for 17 h per day for 8 weeks. MAO-A activity and protein levels were measured immediately after exposure, acute withdrawal (24 h), protracted withdrawal (4 day), and protracted abstinence (3 weeks) (n = 16/group; 8 alcohol exposed, 8 control). ResultsChronic ethanol vapor exposure significantly elevated MAO-A activity and protein levels in the PFC and ACC at 24-h withdrawal (multivariate analysis of variance (MANOVA), activity: F2,13 = 3.82, p = .05, protein: F2,13 = 5.13, p = .02). There were no significant changes in MAO-A level or activity at other timepoints. ConclusionsThe results of this study suggest a causal relationship between acute alcohol withdrawal and elevated MAO-A levels and activity, clarifying the observation of greater MAO-A binding in human alcohol withdrawal. This has important implications for developing methods of targeting MAO-A and/or sequelae of its dysregulation in alcohol dependence.

Antidepressant Effects of Vaccinium bracteatum via Protection Against Hydrogen Peroxide-Induced Oxidative Stress and Apoptosis.

The present study evaluates the anti-oxidative stress activity of Vaccinium bracteatum Thunb. fruit extract (VBFW) to identify the mechanisms responsible for its antidepressant-like effects. To evaluate the antidepressant and anti-oxidant effects of VBFW, malondialdehyde (MDA), serotonin transporter (SERT), and monoamine oxidase A (MAO-A) levels were measured in a mouse model of chronic restraint stress (CRS). The underlying mechanisms preventing oxidative stress and neuronal apoptosis were investigated using in vitro models of hydrogen peroxide (H2O[Formula: see text]-induced neuronal damage. The results showed that VBFW treatment (200[Formula: see text]mg/kg) significantly reduced MDA, SERT, and MAO-A levels in the prefrontal cortex of CRS mice. Furthermore, VBFW (30[Formula: see text][Formula: see text]g/mL) exhibited protective effects against H2O2-induced cell death via inhibition of the H2O2-induced increase in Bax and decrease in Bcl-2 levels within the mitochondria of SH-SY5Y cells. Furthermore, VBFW (10 and 30[Formula: see text][Formula: see text]g/mL) exerted protective effects against H2O2-induced cell death through inhibition of key mitochondria-associated apoptotic proteins such as cytochrome c, caspase-3 and PARP. Additionally, VBFW (10 and 30[Formula: see text][Formula: see text]g/mL) could improve the activity of anti-oxidant enzymes (such as SOD and catalase) in H2O2-treated SH-SY5Y cells. These results suggest that the antidepressant and anti-oxidant effects of VBFW might be mediated by the regulation of SERT and MAO-A, and possibly associated with regulation of oxidative stress-induced apoptosis.

Decreased Monoamine Oxidase A Expression and Activity in the Bladders of Rats With Partial Outlet Obstruction

To investigate changes in expression and activity of monoamine oxidase A (MAO-A) in rats with partial bladder outlet obstruction (pBOO). Previous studies suggested that monoamines, such as serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline, are involved in bladder hyperactivity secondary to pBOO. However, little is known about the role of MAO-A, an enzyme oxidizing 5-hydroxytryptamine and noradrenalin, in the pathogenesis. Female Sprague Dawley rats were subjected to sham or pBOO operations for 7 days, then their bladders were isolated. MAO-A protein levels in the bladder were examined by Western blotting. MAO-A activity was measured by the commercially available MAO-Glo Assay kit. In addition, MAO-A distribution in the bladder was examined by immunohistochemistry. Weights of the bladders from rats with pBOO were increased about 3.5-fold, compared with those from sham rats. Significant decreases in MAO-A protein and activity levels were observed in whole bladder of rats with pBOO compared with those of sham rats. By immunohistochemistry, it was firstly demonstrated that MAO-A was predominantly expressed in the detrusor layer of the sham rat bladders. The intensity of staining was decreased after pBOO operation. We demonstrated, for the first time, the distribution of MAO-A in the bladder and the pathologic changes in MAO-A protein and activity levels in rats with pBOO. This marked decrease in MAO-A potentially resulting in increased monoamine levels, especially in the detrusor of rat bladder, might be a key factor explaining the mechanism of bladder overactivity associated with pBOO.

Paradoxical sleep deprivation modulates depressive-like behaviors by regulating the MAOA levels in the amygdala and hippocampus

Paradoxical sleep is closely associated with depression, and brain monoamine oxidase A (MAOA) plays an important role in depression. However, the precise relationship between sleep and depression and the role of MAOA in this process remains unknown. Therefore, we established a paradoxical sleep deprivation model using the “multiple small platforms over water” protocol. Mice deprived of paradoxical sleep for 3days showed no depressive-like behaviors; however, mice deprived of paradoxical sleep deprivation for 5days (P5d) showed decreased locomotive activity in the first 3days after P5d. Additionally, the P5d mice showed depressive-like behaviors one week after P5d, with a longer immobility time and a decreased sucrose preference rate. In addition, the levels of the MAOA protein and mRNA in the amygdala and hippocampus significantly increased. Furthermore, the immobility time and sucrose preference rate of P5d mice recovered when the mice were injected with phenelzine. The P5d mice displayed depressive-like behaviors, which were likely modulated by the MAOA levels in the amygdala and hippocampus.

Polymorphisms in the canine monoamine oxidase a (MAOA) gene: identification and variation among five broad dog breed groups

BackgroundIn humans, reduced activity of the enzyme monoamine oxidase type A (MAOA) due to genetic polymorphisms within the MAOA gene leads to increased brain neurotransmitter levels associated with aggression. In order to study MAOA genetic diversity in dogs, we designed a preliminary study whose objectives were to identify novel alleles in functionally important regions of the canine MAOA gene, and to investigate whether the frequencies of these polymorphisms varied between five broad breed groups (ancient, herding, mastiff, modern European, and mountain). Fifty dogs representing these five breed groups were sequenced.ResultsA total of eleven polymorphisms were found. Seven were single nucleotide polymorphisms (SNPs; two exonic, two intronic and three in the promoter), while four were repeat intronic variations. The most polymorphic loci were repeat regions in introns 1, 2 (7 alleles) and 10 (3 alleles), while the exonic and the promoter regions were highly conserved. Comparison of the allele frequencies of certain microsatellite polymorphisms among the breed groups indicated a decreasing or increasing trend in the number of repeats at different microsatellite loci, as well as the highest genetic diversity for the ancient breeds and the lowest for the most recent mountain breeds, perhaps attributable to canine domestication and recent breed formation. While a specific promoter SNP (−212A > G) is rare in the dog, it is the major allele in wolves. Replacement of this ancestral allele in domestic dogs may lead to the deletion of heat shock factor binding sites on the MAOA promoter.ConclusionsDogs exhibit significant variation in certain intronic regions of the MAOA gene, while the coding and promoter regions are well-conserved. Distinct genetic differences were observed between breed groups. Further studies are now required to establish whether such polymorphisms are associated in any way with MAOA level and canine behaviour including aggression.

5,7-Dimethoxycoumarin prevents chronic mild stress induced depression in rats through increase in the expression of heat shock protein-70 and inhibition of monoamine oxidase-A levels.

The current study was aimed to investigate the role of 5,7-dimethoxycoumarin in the prevention of chronic mild stress induced depression in rats. The chronic mild stress rat model was prepared using the known protocols. The results from open-field test showed that rats in the chronic mild stress group scored very low in terms of crossings and rearings than those of the normal rats. However, pre-treatment of the rats with 10 mg/kg doses of 5,7-dimethoxycoumarin prevented decline in the locomotor activity by chronic mild stress. The level of monoamine oxidase-A in the chronic mild stress rat hippocampus was markedly higher. Chronic mild stress induced increase in the monoamine oxidase-A level was inhibited by pre-treatment with 10 mg/kg doses of 5,7-dimethoxycoumarin in the rats. Chronic mild stress caused a marked increase in the level of caspase-3 mRNA and proteins in rat hippocampus tissues. The increased level of caspase-3 mRNA and protein level was inhibited by treatment of rats with 5,7-dimethoxycoumarin (10 mg/kg). 5,7-Dimethoxycoumarin administration into the rats caused a marked increase in the levels of heat shock protein-70 mRNA and protein. The levels of heat shock protein-70 were markedly lower both in normal and chronic mild stress groups of rats compared to the 5,7-dimethoxycoumarin treated groups. Thus 5,7-dimethoxycoumarin prevented the chronic mild stress induced depression in rats through an increase in the expression of heat shock protein-70 and inhibition of monoamine oxidase-A levels.

Amphetamine manipulates monoamine oxidase-A level and behavior using theranostic aptamers of transcription factors AP-1/NF-kB.

BackgroundMonoamine oxidase (MAO) enzymes play a critical role in controlling the catabolism of monoamine neurotransmitters and biogenic trace amines and behavior in humans. However, the mechanisms that regulate MAO are unclear. Several transcription factor proteins are proposed to modulate the transcription of MAO gene, but evidence supporting these hypotheses is controversial. We aimed to investigate the mechanism of gene transcription regulator proteins on amphetamine-induced behavior. We applied aptamers containing a DNA binding sequence, as well as a random sequence (without target) to study the modulation of amphetamine-induced MAO levels and hyperactivity in living mice.MethodsWe pretreated in adult male C57black6 mice (Taconic Farm, Germantown, NY) (n ≥ 3 litters at a time), 2 to 3 months of age (23 ± 2 gm body weight) with double-stranded (ds) DNA aptamers with sequence specific to activator protein-1 (5ECdsAP1), nuclear factor-kappa beta (5ECdsNF-kB), special protein-1 (5ECdsSP-1) or cyclicAMP responsive element binding (5ECdsCreB) protein binding regions, 5ECdsRan [a random sequence without target], single-stranded AP-1 (5ECssAP-1) (8 nmol DNA per kg) or saline (5 μl, intracerebroventricular [icv] injection) control before amphetamine administration (4 mg/kg, i.p.). We then measured and analyzed locomotor activities and the level of MAO-A and MAO-B activity.ResultsIn the pathological condition of amphetamine exposure, we showed here that pretreatment with 5ECdsAP1 and 5ECdsNF-kB reversed the decrease of MAO-A activity (p < 0.05, t test), but not activity of the B isomer (MAO-B), in the ventral tegmental area (VTA) and substantia nigra (SN) of C57black6 mice. The change in MAO-A level coincided with a reversed amphetamine-induced restless behavior of mice. Pretreatments with saline, 5ECdsCreB, 5ECdsSP-1, 5ECdsRan or 5ECssAP-1 had no effect.ConclusionOur data lead us to conclude that elevation of AP-1 or NF-kB indirectly decreases MAO-A protein levels which, in turn, diminishes MAO-A ability in the VTA of the mesolimbic dopaminergic pathway that has been implicated in cells under stress especially in the SN and VTA. This study has implications for design for the treatment of drug exposure and perhaps Parkinson’s dementia.

Sensitive and Selective Ratiometric Fluorescence Probes for Detection of Intracellular Endogenous Monoamine Oxidase A.

Monoamine oxidase A (MAO-A) is known to widely exist in most cell lines in the body, and its dysfunction (unusually high or low levels of MAO-A) is thought to be responsible for several psychiatric and neurological disorders. Thus, a sensitive and selective method for evaluating the relative MAO-A levels in different live cells is urgently needed to better understand the function of MAO-A, but to our knowledge such a method is still lacking. Herein, we rationally design two new ratiometric fluorescence probes (1 and 2) that can sensitively and selectively detect MAO-A. The probes are constructed by incorporating a recognition group of propylamine into the fluorescent skeleton of 1,8-naphthalimide, and the detection mechanism is based on amine oxidation and β-elimination to release the fluorophore (4-hydroxy-N-butyl-1,8-naphthalimide), which is verified by HPLC analysis. Reaction of the probes with MAO-A produces a remarkable fluorescence change from blue to green, and the ratio of fluorescence intensity at 550 and 454 nm is directly proportional to the concentration of MAO-A in the ranges of 0.5-1.5 and 0.5-2.5 μg/mL with detection limits of 1.1 and 10 ng/mL (k = 3) for probes 1 and 2, respectively. Surprisingly, these probes show strong fluorescence responses to MAO-A but almost none to MAO-B (one of two isoforms of MAO), indicating superior ability to distinguish MAO-A from MAO-B. The high specificity of the probes for MAO-A over MAO-B is further supported by different inhibitor experiments. Moreover, probe 1 displays higher sensitivity than probe 2 and is thus investigated to image the relative MAO-A levels in different live cells, such as HeLa and NIH-3T3 cells. It is found that the concentration of endogenous MAO-A in HeLa cells is approximately 1.8 times higher than that in NIH-3T3 cells, which is validated by the result from an ELISA kit. Additionally, the proposed probes may find more uses in the specific detection of MAO-A between the two isoforms of MAO, thereby promoting our understanding of the behavior and function of MAO-A in living biosystems.

Association of ventral striatum monoamine oxidase-A binding and functional connectivity in antisocial personality disorder with high impulsivity: A positron emission tomography and functional magnetic resonance imaging study

Impulsivity is a core feature of antisocial personality disorder (ASPD) associated with abnormal brain function and neurochemical alterations. The ventral striatum (VS) is a key region of the neural circuitry mediating impulsive behavior, and low monoamine oxidase-A (MAO-A) level in the VS has shown a specific relationship to the impulsivity of ASPD. Because it is currently unknown whether phenotypic MAO-A markers can influence brain function in ASPD, we investigated VS MAO-A level and the functional connectivity (FC) of two seed regions, superior and inferior VS (VSs, VSi). Nineteen impulsive ASPD males underwent [11C] harmine positron emission tomography scanning to measure VS MAO-A VT, an index of MAO-A density, and resting-state functional magnetic resonance imaging that assessed the FC of bilateral seed regions in the VSi and VSs. Subjects also completed self-report impulsivity measures. Results revealed functional coupling of the VSs with bilateral dorsomedial prefrontal cortex (DMPFC) that was correlated with VS MAO-A VT (r=0.47, p=0.04), and functional coupling of the VSi with right hippocampus that was anti-correlated with VS MAO-A VT (r=−0.55, p=0.01). Additionally, VSs-DMPFC FC was negatively correlated with NEO Personality Inventory-Revised impulsivity (r=−0.49, p=0.03), as was VSi-hippocampus FC with Barratt Impulsiveness Scale-11 motor impulsiveness (r=−0.50, p=0.03). These preliminary results highlight an association of VS MAO-A level with the FC of striatal regions linked to impulsive behavior in ASPD and suggest that phenotype-based brain markers of ASPD have relevance to understanding brain function.

Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer.

Background:Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normal prostate glands. However, the relationship between survivin and MAOA in PCa is unclear.Methods:We examined MAOA expression in the prostate lobes of a conditional PTEN-deficient mouse model mirroring human PCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We further evaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells.Results:Survivin and MAOA levels are both increased in clinical PCa tissues and significantly associated with patients' survival. Survivin depletion delayed MAOA increase during PCa progression, and silencing MAOA decreased survivin expression. The combination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition of PCa cell growth, migration and invasion with concomitant decrease in survivin and MMP-9 levels.Conclusions:There is a positive feedback loop between survivin and MAOA expression in PCa. Considering that survivin suppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support a rapid translation of this combination to clinical practice.

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [(11)C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=-0.50 to -0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.

Plant-derived flavanol (-)epicatechin mitigates anxiety in association with elevated hippocampal monoamine and BDNF levels, but does not influence pattern separation in mice.

Flavanols found in natural products such as cocoa and green tea elicit structural and biochemical changes in the hippocampus, a brain area important for mood and cognition. Here, we evaluated the outcome of daily consumption of the flavanol (−)epicatechin (4 mg per day in water) by adult male C57BL/6 mice on measures of anxiety in the elevated plus maze (EPM) and open field (OF). Furthermore, pattern separation, the ability to distinguish between closely spaced identical stimuli, considered to be mediated by the hippocampal dentate gyrus (DG), was tested using the touchscreen. To investigate mechanisms through which (−)epicatechin may exert its effects, mice were injected with bromodeoxyuridine (50 mg kg−1) to evaluate adult hippocampal neurogenesis. In addition, monoaminergic and neurotrophin signaling pathway proteins were measured in tissue derived from subject cortices and hippocampi. Flavanol consumption reduced anxiety in the OF and EPM. Elevated hippocampal and cortical tyrosine hydroxylase, downregulated cortical monoamine oxidase-A levels, as well as increased hippocampal brain-derived neurotrophic factor (BDNF) and pro-BDNF support the flavanol's anxiolytic effects. In addition, elevated pAkt in hippocampus and cortex was observed. (−)Epicatechin ingestion did not facilitate touchscreen performance or DG neurogenesis, suggesting a non-neurogenic mechanism. The concurrent modulation of complementary neurotrophic and monoaminergic signaling pathways may contribute to beneficial mood-modulating effects of this flavanol.