Effect Of Monoamine Oxidase Research Articles

P-313 Dysregulation of endometrial stromal serotonin homeostasis impairs decidualization in patients with recurrent implantation failure via phosphatidylcholine metabolism

Abstract Study question Does abnormal serotonin homeostasis contribute to impaired endometrial decidualization in patients with recurrent implantation failure (RIF)? Summary answer Abnormal serotonin homeostasis in patients with RIF, which is accompanied by decreased expression of monoamine oxidase (MAO), affects decidualization of endometrial stromal cells. What is known already Previous studies have found that the expression of MAO, which metabolizes serotonin, is reduced in the endometrium of patients with RIF, and serotonin can induce disruption of implantation in rats. However, whether abnormal serotonin homeostasis leads to impaired decidualization in patients with RIF and the mechanism remains unclear. Study design, size, duration Endometrial samples from 31 patients with RIF and 31 fertile patients were used to investigate the expression levels of MAOA, MAOB, and serotonin. We isolated human endometrial stromal cells to investigate the role of MAOA, MAOB and serotonin in inducing decidualization in vitro and further explored the mechanism using RNA-seq and LC/MS analyses. Participants/materials, setting, methods The levels of serotonin in the endometrium of patients with RIF were detected by ELISA and immunohistofluorescence, and the key genes of abnormal serotonin metabolism were analyzed combined with single-cell sequencing data. The effects of MAO on the decidualization of stromal cells were investigated using human endometrial stromal cells in vitro induced decidualization model and mouse artificially induced decidualization model. The potential mechanisms of MAO regulating decidualization were explored by RNA-seq and LC/MS analysis. Main results and the role of chance We found that women with RIF have abnormal serotonin metabolism in the endometrium and attenuated MAO in endometrial stromal cells. Endometrial decidualization was accompanied by increased MAO in vivo and in vitro. Attenuated MAO caused increased local serotonin content in the endometrium, impairing stromal cell decidualization. RNA-seq and LC/MS analyses showed that abnormal lipid metabolism, especially phosphatidylcholine metabolism, was involved in MAO-deficiency induced defective decidualization. Furthermore, decidualization defects were rescued by phosphatidylcholine supplementation. Limitations, reasons for caution This study found that impaired serotonin metabolic homeostasis and abnormally reduced MAO expression were one of the reasons for repeated implantation failure. However, the source and other potential function of serotonin in the endometrium remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of serotonin homeostasis in human endometrial decidualization and provides new biomarkers or targets for the treatment of patients with RIF. Trial registration number not applicable

P-313 Dysregulation of endometrial stromal serotonin homeostasis impairs decidualization in patients with recurrent implantation failure via phosphatidylcholine metabolism

Abstract Study question Does abnormal serotonin homeostasis contribute to impaired endometrial decidualization in patients with recurrent implantation failure (RIF)? Summary answer Abnormal serotonin homeostasis in patients with RIF, which is accompanied by decreased expression of monoamine oxidase (MAO), affects decidualization of endometrial stromal cells. What is known already Previous studies have found that the expression of MAO, which metabolizes serotonin, is reduced in the endometrium of patients with RIF, and serotonin can induce disruption of implantation in rats. However, whether abnormal serotonin homeostasis leads to impaired decidualization in patients with RIF and the mechanism remains unclear. Study design, size, duration Endometrial samples from 31 patients with RIF and 31 fertile patients were used to investigate the expression levels of MAOA, MAOB, and serotonin. We isolated human endometrial stromal cells to investigate the role of MAOA, MAOB and serotonin in inducing decidualization in vitro and further explored the mechanism using RNA-seq and LC/MS analyses. Participants/materials, setting, methods The levels of serotonin in the endometrium of patients with RIF were detected by ELISA and immunohistofluorescence, and the key genes of abnormal serotonin metabolism were analyzed combined with single-cell sequencing data. The effects of MAO on the decidualization of stromal cells were investigated using human endometrial stromal cells in vitro induced decidualization model and mouse artificially induced decidualization model. The potential mechanisms of MAO regulating decidualization were explored by RNA-seq and LC/MS analysis. Main results and the role of chance We found that women with RIF have abnormal serotonin metabolism in the endometrium and attenuated MAO in endometrial stromal cells. Endometrial decidualization was accompanied by increased MAO in vivo and in vitro. Attenuated MAO caused increased local serotonin content in the endometrium, impairing stromal cell decidualization. RNA-seq and LC/MS analyses showed that abnormal lipid metabolism, especially phosphatidylcholine metabolism, was involved in MAO-deficiency induced defective decidualization. Furthermore, decidualization defects were rescued by phosphatidylcholine supplementation. Limitations, reasons for caution This study found that impaired serotonin metabolic homeostasis and abnormally reduced MAO expression were one of the reasons for repeated implantation failure. However, the source and other potential function of serotonin in the endometrium remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of serotonin homeostasis in human endometrial decidualization and provides new biomarkers or targets for the treatment of patients with RIF. Trial registration number not applicable Study funding No Funding source Funding by national/international organization(s)

Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells.

Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly expressed in high grade prostate cancer and modulates tumorigenesis and progression in prostate cancer. Here, we investigated the potential role of MAOA inhibitors (MAOAIs) in relation to the androgen receptor (AR) pathway and resistance to antiandrogen treatment in prostate cancer. We examined MAOA expression and the effect of MAOI treatment in relation to AR-targeted treatments using the LNCaP, C4-2B, and 22Rv1 human prostate cancer cell lines. MAOA, AR-full length (AR-FL), AR splice variant 7 (AR-V7), and PSA expression was evaluated in the presence of MAOAIs (clorgyline, phenelzine), androgenic ligand (R1881), and antiandrogen (enzalutamide) treatments. An enzalutamide resistance cell line was generated to test the effect of MAOAI treatment in this model. We observed that MAOAIs, particularly clorgyline and phenelzine, were effective at decreasing MAOA activity in human prostate cancer cells. MAOAIs significantly decreased growth of LNCaP, C4-2B, and 22Rv1 cells and produced additive growth inhibitory effects when combined with enzalutamide. Clorgyline decreased expression of AR-FL and AR-V7 in 22Rv1 cells and was effective at decreasing growth of an enzalutamide-resistant C4-2B cell line with increased AR-V7 expression. MAOAIs decrease growth and proliferation of androgen-sensitive and castration-resistant prostate cancer cells. Clorgyline, in particular, decreases expression of AR-FL and AR-V7 expression and decreases growth of an enzalutamide-resistant cell line. These findings provide preclinical validation of MAOA inhibitors either alone or in combination with antiandrogens for therapeutic intent in patients with advanced forms of prostate cancer.

The effect of Monoamine oxidase A inhibition on experimentally induced pulmonary arterial hypertension

The effect of Monoamine oxidase A inhibition on experimentally induced pulmonary arterial hypertension

Effect of monoamine oxidase A on anti-cancer immunity of CD8+ T cells in cholangiocarcinoma

Objective To investigate the effect of monoamine oxidase A (MAOA) in cholangiocarcinoma on anti-tumor immunity of CD8+ T cells. Methods We established stably inducible MAOA expression human cholangiocarcinoma cell lines by transfecting Tet-on 3G system. CD8+ T cells were isolated from peripheral blood donated by healthy donors. After coculture with above celllines for 48 h, CD8+ T cells were analyzed by flow cytometry to detect the expression of granzyme B, perforin, programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), as well as apoptosis rate. Enzyme linked immunosorbent assay (ELISA) was applied to assess the excretion of IFN-γ from CD8+ T cells. Lactate dehydrogenase (LDH) test was performed to evaluate the cytotoxicity against the mixed cultured tumor cells by CD8+ T cells. Results CD8+ T cells in mock transfected groups expressed lower level of granzyme B (44.2% vs. 51.5%, P=0.000), perforin (51.8% vs. 74.3%, P=0.000), expressed higher level of PD-1 and CTLA-4 (81.70% vs. 21.30%, P=0.000; 16.00% vs. 8.49%, P=0.000 respectively), secreted fewer IFN-γ (7 562.0±927.5) pg/ml vs. (10 107.0±1 162.0) pg/ml, P=0.229) and had a higher apoptosis rate (26.43% vs. 13.35%, P=0.000), and the cytotoxicity CD8+ T cells was also suppressed [(12.70±1.49)% vs. (22.88±2.93)%, P=0.036]. Conclusion Down-regulation of MAOA in cholangiocarcinoma would impede anti-tumour immunity of CD8+ T cells. Key words: Monoamine oxidase A; Cholangiocarcinoma; CD8+ T cells; Tumor immunity

The interactive effects of monoamine oxidase A (MAOA) gene and peer victimization on depressive symptoms in early adolescent boys: The moderating role of catechol-O-methyltransferase (COMT) gene

The interactive effects of monoamine oxidase A (MAOA) gene and peer victimization on depressive symptoms in early adolescent boys: The moderating role of catechol-O-methyltransferase (COMT) gene

Effect of monoamine oxidase- A on the anti- tumor immunity of tumor- associated macrophages in biliary tract cancers

Objective To investigate the effect of monoamine oxidase- A(MAO- A)in biliary tract cancers(BTCs) on the immunity of tumor- associated macrophages. Methods MAO- A expression plasmid and control plasmid were constructed and transiently transfected into BTC cell lines respectively. Macrophages were derived from peripheral blood mononuclear cells donated by healthy volunteers. Macrophages were then cocultured with aforementioned transfected cancer cell lines for 48 h respectively, Western blotting and enzyme linked immunosorbent assay(ELISA) were applied to assess the expression of immune effector proteins and the excretion of cytokines from cocultured macrophages.24 h priming of macrophages with human recombinant interferon-γ(IFN -γ) were performed after their first stage of coculture; then the second stage of coculture with corresponding transfected cancer cell lines for 48 h were followed.Flow cytometry was employed to detect necrosis and apotosis of cancer cells induced by cocultured macrophages. Results The expression of MAO- A was down- regulated in BTC cell lines, which polarized the cocultured macrophages into M2 type tumor- associated macrophages, and promoted their excretion of interleukin(IL)- 10 and expression of PD- L1, while suppressed their excretion of tumor necrosis factor-α(TNF-α), IL- 1βand IL-12p70(18.8±2.3 vs.31.7±1.9,75.0±0.4 vs.150.2±17.0 and 49.1±15.2 vs.135.2±1.0, respectively, P<0.05),as well as the expression of Human leukocyte antigen- DR(HLA- DR).On the contrary, however, macrophages cocultured with MAO- A overexpressing BTC cells exhibited pro- inflammatory phenotype(M1 type) which opposite to above suppressive immunity phenotype (M2 type).After priming of IFN-γ, macrophages cocultured with MAO- A overexpressing BTC cells induced tumor necrosis and apoptosis more effectively than those cocultured with control BTC cells[(84.85±5.66)% vs.(1.56±0.46)% and(76.73±6.31)% vs.(1.28±0.57)%, respectively, P<0.05]. Conclusion Down- regulation of MAO- A in BTC can promote the development of M2 type tumor- associated macrophages, while restoration of MAO- A in BTC can recover antitumor immunity of macrophages.Present study supports MAO- A as a promising target in the immunotherapy of BTC. Key words: Monoamine oxidase-A; Biliary tract cancer; Immune microenvironment; Tumor-associated macrophages; Tumor immune escape

The moderating effect of monoamine oxidase A gene polymorphism in relationship between childhood abuse of male adolescents and externalizing behaviors

Objective To explore the relationship between male adolescents' childhood abuse and externalizing behaviors, and the moderating effect of monoamine oxidase A (MAOA)gene promoter region variable number tandem repeat (VNTR)polymorphism. Methods Through random cluster sampling, 352 Han male middle school students from Changsha were tested by Achenbach child behavior checklist-youth self reports (CBCL-YSR)and childhood trauma questionnaire-28 item short form(CTQ-SF), their MAOA genotypes were also identified. A hierarchical multiple regression analysis was used to test the moderating effect. Results (1) Compared participates with high activity MAOA gene and that with low activity MAOA gene, there were no significant differences on age((15.82±1.52) vs (15.94±1.62)), externalizing behaviors((15.13±10.14) vs (14.33±9.70)), total abuse((52.59±10.46) vs (51.39±7.56)), emotional abuse((7.63±3.31) vs ( 7.11±2.68)), physical abuse((6.40±2.82) vs (6.12±2.05)), sexual abuse((6.42±3.24) vs (5.94±1.72)), emotional neglect((13.44±5.12) vs (13.16±4.83)), physical neglect((10.27±2.64) vs (10.44±2.53))(t=-1.789~0.678, P>0.05). (2)Except emotional neglect and physical neglect, emotional abuse, physical abuse and sexual abuse could predict externalizing behaviors(Sβ=0.141~0.347, P 0.05). There was a significant interaction between MAOA gene and emotional abuse(Sβ=-0.148, P 0.05). Conclusion MAOA gene polymorphism can moderate the relationship between male adolescents' childhood emotional abuse and externalizing behaviors. Key words: Externalizing behavior; Monoamine oxidase A gene; Childhood abuse; Moderating effort

Neural progenitor cells are protected against MPTP by MAO-B inhibitors

Neurotoxic effects of MPTP on the nigrostriatal dopaminergic system are thought to be initiated by 1-methyl-4-phenylpyridinium (MPP+), a metabolite formed by the monoamine oxidase (MAO)-B-mediated oxidation of MPTP. We previously reported that the administration of MPTP induced apoptosis in migrating neuroblasts (neural progenitor cells, NPCs) in adult mice. To determine whether MAO-B is also involved in the neurotoxicity of MPTP to NPCs, this study looked at the effects of MAO B inhibitors, R(−)-deprenyl (deprenyl) and N-(2-aminoethyl)-4-chlorobenzamide (Ro 16-6491), both of which protect the dopaminergic system against MPTP. Few apoptotic cells were found in saline- or MAO-B inhibitor-treated animals but MPTP markedly induced apoptosis in the subventricular zone (SVZ) and rostral migratory stream (RMS) after 1 day. When mice were pretreated with deprenyl or Ro 16-6491, not only nigrostriatal dopamine levels but also NPCs were significantly protected against MPTP. In addition, MPTP-induced apoptosis was found in both juvenile (postnatal 21 days) and older (12 months old) mice, suggesting NPCs to be different from the dopamine system, which has been thought to exhibit age-dependent susceptibility to MPTP.

The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease.

The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Monoamine Oxidase in Neuropsychiatry and Behavior

Monoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, designated “MAO A” and “MAO B,” have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A exhibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston 1968), whereas MAO B has a higher affinity for PEA, benzylamine, and the inhibitor deprenyl (Knoll and Magyar 1972).

Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period.

Genetic inactivation of monoamine oxidase A (MAOA) in C3H/HeJ mice causes a complete absence of barrels in the somatosensory cortex, and similar alterations are caused by pharmacological inhibition of MAOA in wild type mice. To determine when and how MAOA inhibition affects the development of the barrel field, the MAOA inhibitor clorgyline was administered to mice of the outbred strain OF1 for various time periods between embryonic day 15 (E15) and postnatal day 7 (P7), and the barrel fields were analyzed with cytochrome oxidase and Nissl stains in P10 and adult mice. High-pressure liquid chromatography measures of brain serotonin (5-HT) showed three- to eightfold increases during the periods of clorgyline administration. Perinatal mortality was increased and weight gain was slowed between P3 and P6. Clorgyline treatments from E15 to P7 or from P0 to P7 disrupted the formation of barrels in the anterior snout representation and in parts of the posteromedial barrel subfield (PMBSF). Treatments from P0 to P4 caused similar although less severe barrel field alterations. Clorgyline treatments only during embryonic life or starting on P4 caused no detectable abnormalities. In cases with barrel field alterations, a rostral-to-caudal gradient of changes was noted: Rostral barrels of the PMBSF were most frequently fused and displayed an increased size tangentially. Thus, MAOA inhibition resulting in increased brain levels of 5-HT affects barrel development during the entire first postnatal week, with a sensitive period between P0 and P4. The rostral-to-caudal gradient of changes in the barrel field parallels known developmental gradients in the sensory periphery and in the maturation thalamocortical afferents. The observed barrel fusions could correspond to a default in the initial segregation of thalamic fibers or to a continued, exuberant growth of these fibers that overrides the tangential domain that is normally devoted to individual whiskers.

Effects of monoamine oxidase and catechol- O-methyltransferase inhibition on dopamine turnover: A PET study with 6-[ [formula omitted]] l-DOPA

The consequences of monoamine oxidase and catechol- O-methyltransferase inhibition on the effective turnover of dopamine were investigated using 6-[ 18 F ] l-3-4-dihydroxyphenylalanine (6-[ 18 F ] l-DOPA) and positron emission tomography. The effective dopamine turnover was expressed as the ratio between the rate of reversibility of 6-[ 18 F ] l-DOPA trapping ( k loss) and the rate of uptake of 6-[ 18 F ] l-DOPA ( K i) in the striatum of normal cynomolgus monkeys. The monkeys received 6-[ 18 F ] l-DOPA scans, untreated or after pretreatment with either the peripheral catechol- O-methyltransferase inhibitor nitecapone; the peripheral and central catechol- O-methyltransferase inhibitor tolcapone; the monoamine oxidase inhibitors deprenyl or pargyline; a combination of tolcapone and the monoamine oxidase inhibitors. Tolcapone alone or combined with the monoamine oxidase inhibitors produced a significant decrease in the dopamine turnover (55 to 65%). Neither nitecapone nor monoamine oxidase inhibition alone produced significant changes. These results may have implications for the use of central catechol- O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.

Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior.

The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10 mg/kg Ro 41-1049 increased both parameters; inhibition of COMT with 30 mg/kg Ro 40-7592 had a similar effect. In contrast, inhibition of MAO-B with 10 mg/kg Ro 19-6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10 mg/kg of the MAO-B inhibitor, Ro 19-6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of l-DOPA-treated monkeys

The effects of monoamine oxidase (MAO) inhibitors on the metabolism of dopamine synthesized from exogenous l-DOPA were investigated in the striatum and substantia nigra of squirrel monkeys. Administration of a single dose of l-DOPA (methyl ester, 40 mg/kg, i.p.) caused a significant increase in the levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and in the DOPAC/dopamine ratio in the putamen, caudate and substantia nigra. These changes were more pronounced in the substantia nigra than in the striatum and within the striatum of l-DOPA-treated monkeys, levels of dopamine and its metabolites were higher in the putamen than in the caudate nucleus. When l-DOPA treatment was preceded by the injection of clorgyline or deprenyl at a concentration (1 mg/kg) which selectively inhibited MAO A or MAO B, respectively, striatal dopamine was increased while the striatal DOPAC and HVA levels and DOPAC/dopamine ratio were significantly reduced as compared to the values obtained with l-DOPA alone. The two MAO inhibitors also counteracted the increase in the DOPAC and HVA levels and DOPAC/dopamine ratio induced by l-DOPA in the substantia nigra. Thus, both MAO A and MAO B contribute to the metabolism of dopamine when higher levels of this neurotransmitter are generated from l-DOPA in the squirrel monkey. The extent of reduction of dopamine catabolism (as assessed by the decrease in DOPAC and HVA levels) in the striatum and substantia nigra was similar with clorgyline and deprenyl even if the ratio MAO A/MAO B was approximately 1 to 10. This indicates that, though catalyzed by both MAO A and MAO B, dopamine deamination following treatment with l-DOPA preferentially involves MAO A.

Kinetics and metabolism of p-tyramine during monoamine oxidase inhibition by mofegiline

The effects of monoamine oxidase B (MAO-B) inhibition by mofegiline on the pharmacokinetics of p-tyramine and its major metabolite, p-hydroxyphenylacetic acid, were investigated in 24 healthy male volunteers. p-Tyramine doses were administered before and after a 14-day treatment period of 1, 12, or 24 mg mofegiline or placebo. Normalized p-tyramine for area under the plasma concentration-time curve after treatment were not significantly different from their respective before-treatment values for any of the dose groups. The relative bioavailability of p-tyramine after treatment was not significantly different from before treatment, although a tendency to a greater bioavailability was seen with the 12 and 24 mg doses. There were no significant differences between pharmacokinetic parameters for p-hydroxyphenylacetic acid. The data suggest that mofegiline maintains its selectivity for MAO-B in the intestine and liver at doses up to and including 24 mg. Therefore these doses would not be expected to be associated with the hypertensive crises normally associated with the "cheese effect."

The effects of monoamine oxidase B inhibition on dopamine metabolism in rats with nigro-striatal lesions

The purpose of this study was to examine whether monoamine oxidase type B (MAO-B) has a role in striatal dopamine metabolism in animals with a unilateral lesion of the medial forebrain bundle, and whether 2-phenylethylamine (PE) could have a role in amplification of dopamine (DA) responses in DA depleted striatum. Inhibition of MAO-B did not alter DA metabolism in lesioned striata. PE accumulation decreased with loss of DA as long as there was no DA dysfunction. In lesioned striata with dysfunction of DA transmission at the synaptic level, PE accumulation increased, suggesting a compensatory increase in PE synthesis. This increase in PE levels does not appear to be mediated by an increase in the total striatal aromatic L-amino acid decarboxylase (AADC) activity. We conclude that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that PE could be involved in the antiparkinsonian action of MAO-B inhibitors.

Effect of monoamine oxidase A and B inhibition on the uptake and metabolism of serotonin within serotonergic neurons of rat brain

The effects of inhibiting monoamine oxidase (MAO) A and B on metabolism and uptake of serotonin (5-HT) in serotonergic synaptosomes were studied. To avoid contamination by extrasynaptosomal MAO, synaptosomes were separated from other components of rat brains by discontinuous sucrose density gradient centrifugation. Kinetic analysis of 5-HT uptake demonstrated that 5-HT was selectively transported into serotonergic synaptosomes through the high affinity 5-HT uptake process. Selectivity of the uptake and subsequent deamination of 5-HT within serotonergic synaptosomes were confirmed using selective and non-selective 5-HT and norepinephrine (NE) uptake inhibitors. MAO inhibitor analysis of 5-HT deamination occurring within serotonergic synaptosomes indicated that, at physiologically relevant concentrations of 5-HT, MAO A deaminates 5-HT, maintaining a low cytoplasmic concentration of 5-HT. When the cytoplasmic concentration of 5-HT is increased above physiologically relevant levels by the inhibition of MAO A, MAO B becomes active. [( 14)C] 5-HT uptake into synaptosomes was reduced by decreasing the V( max) of [(14)C] 5-HT uptake. One mechanism for a decrease in the V(max) could be the increase in the cytoplasmic concentration of 5-HT.

Regional inhibition of monoamine oxidase activity by administration of clorgyline in rat brain.

The inhibiting effect of monoamine oxidase (MAO) activities towards 5-hydroxytryptamine, dopamine and beta-phenylethylamine by an acute and chronic administration of clorgyline was investigated in five locations of the rat brain. Inhibiting the percentage distributed unevenly in each hypothalamic nucleus and in the circumventricular areas, except the median eminence, the percentages were significantly low as compared with the hypothalamic lateral nucleus. A significant percentage of inhibition for type B MAO towards beta-phenylethylamine was noticed in the chronically administered group. In conclusion, the MAO-inhibiting effect of clorgyline administered intraperitoneally was unevenly distributed in the discrete brain nuclei and the regional difference depended upon the dose and the duration of the clorgyline administration.

Placental monoamine oxidase content and inhibition: Effect of enzyme inhibition on maternofetal transfer of noradrenaline (norepinephrine) in the human placenta in vitro

The effect of monoamine oxidase (MAO) inhibition on maternofetal transfer of noradrenaline (NA) has been investigated in vitro using dual perfusion of isolated human placental lobules. As a first step, placental MAO content and its sensitivity to inhibition by pargyline were assessed in incubation studies of homogenates as well as during perfusion, taking rat liver as reference. Our results show that the human placenta, though it contains as great an enzyme activity as rat liver, was less sensitive to inhibition by pargyline than the latter. MAO inhibition by pargyline significantly reduced the NA clearance from maternal to fetal circulation. Thus the proportion of unmetabolized NA radioactivity in fetal venous samples decreased significantly after pargyline treatment. A concomitant rise in the proportion of mainly O-methylated metabolites was also observed. We speculate that the apparent activation of catechol-O-methyl transferase pathway, observed in our studies on MAO inhibition, may play an important role in limiting NA transfer towards the fetus in toxaemic pregnancies associated with the reduction in placental MAO.