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Concept: Monoamine oxidase

244

Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

Concepts: Neuron, Monoamine oxidase, Serotonin, Stem cell, Monoamine oxidase inhibitor, Progenitor cell, Developmental biology, Cell biology

163

There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B (MAOB) inhibitors. They have been studied for their potential disease-modifying effects in Parkinson’s disease (PD) for over 20 years in various clinical trials. This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD. Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug. Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles, some of which may be insurmountable.

Concepts: Multiple system atrophy, Alzheimer's disease, Parkinsonism, Monoamine oxidase B, Monoamine oxidase, Selegiline, Parkinson's disease, Rasagiline

160

Aims: Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinson’s disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated. Methods: This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity. Results: 247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure. Conclusion: This TQT study demonstrated a favorable cardiac safety profile of rasagiline.

Concepts: Monoamine oxidase, Pulse, Parkinson's disease, Neurotransmitter, Blood, Vital signs, Pharmacology, Blood pressure

149

According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson’s disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intra-neuronal dopamine to DOPAL and may serve as a therapeutic target. The “cheese effect” - paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production has been unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All 3 drugs also increased dopamine and norepinephrine, decreased DOPA, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine auto-oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson’s disease.

Concepts: Epinephrine, Phenethylamine, Monoamine oxidase inhibitors, Rasagiline, Parkinson's disease, Neurotransmitter, Dopamine, Monoamine oxidase

112

A high-calorie diet (HCD) induces two mutually exacerbating effects contributing to diet-induced obesity (DIO): impaired glucose metabolism and increased food consumption. A link between the metabolic and behavioral manifestations is not well understood yet. We hypothesized that chronic inflammation induced by HCD plays a key role in linking together the two components of diet-induced pathology. Based on this hypothesis, we tested if a plasmid (DNA vaccine) encoding p62 (SQSTM1) would alleviate DIO including its metabolic and/or food consumption abnormalities. Previously we reported that injections of the p62 plasmid reduce chronic inflammation during ovariectomy-induced osteoporosis. Here we found that the p62 plasmid reduced levels of pro-inflammatory cytokines IL-1β, IL-12, and INFγ and increased levels of anti-inflammatory cytokines IL-4, IL-10 and TGFβ in HCD-fed animals. Due to this anti-inflammatory response, we further tested whether the plasmid can alleviate HCD-induced obesity and associated metabolic and feeding impairments. Indeed, p62 plasmid significantly reversed effects of HCD on the body mass index (BMI), levels of glucose, insulin and glycosylated hemoglobin (HbA1c). Furthermore, p62 plasmid partially restored levels of the satiety hormone, serotonin, and tryptophan, simultaneously reducing activity of monoamine oxidase (MAO) in the brain affected by the HCD. Finally, the plasmid partially reversed increased food consumption caused by HCD. Therefore, the administering of p62 plasmid alleviates both metabolic and behavioral components of HCD-induced obesity.

Concepts: Enzyme, Obesity, Monoamine oxidase, Insulin, Inflammation, Diabetes mellitus, Body mass index, Nutrition

48

In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes.Molecular Psychiatry advance online publication, 28 October 2014; doi:10.1038/mp.2014.130.

Concepts: Gene, Mental disorder, Antisocial personality disorder, Personality disorder, Monoamine oxidase

40

Medical research is moving toward prevention strategies during prodromal states. Postpartum blues (PPB) is often a prodromal state for postpartum depression (PPD), with severe PPB strongly associated with an elevated risk for PPD. The most common complication of childbearing, PPD has a prevalence of 13%, but there are no widespread prevention strategies, and no nutraceutical interventions have been developed. To counter the effects of the 40% increase in monoamine oxidase A (MAO-A) levels that occurs during PPB, a dietary supplement kit consisting of monoamine precursor amino acids and dietary antioxidants was created. Key ingredients (tryptophan and tyrosine) were shown not to affect their total concentration in breast milk. The aim of this open-label study was to assess whether this dietary supplement reduces vulnerability to depressed mood at postpartum day 5, the typical peak of PPB. Forty-one healthy women completed all study procedures. One group (n = 21) received the dietary supplement, composed of 2 g of tryptophan, 10 g of tyrosine, and blueberry juice with blueberry extract. The control group (n = 20) did not receive any supplement. PPB severity was quantitated by the elevation in depressed mood on a visual analog scale following the sad mood induction procedure (MIP). Following the MIP, there was a robust induction of depressed mood in the control group, but no effect in the supplement group [43.85 ± 18.98 mm vs. 0.05 ± 9.57 mm shift; effect size: 2.9; F(1,39) = 88.33, P < 0.001]. This dietary supplement designed to counter functions of elevated MAO-A activity eliminates vulnerability to depressed mood during the peak of PPB.

Concepts: Amino acid, Sadness, Nutrition, Neurotransmitter, Bipolar disorder, Seasonal affective disorder, Monoamine oxidase, Dietary supplement

30

Psychologists, quality of life and well-being researchers have grown increasingly interested in understanding the factors that are associated with human happiness. Although twin studies estimate that genetic factors account for 35-50% of the variance in human happiness, knowledge of specific genes is limited. However, recent advances in molecular genetics can now provide a window into neurobiological markers of human happiness. This investigation examines association between happiness and monoamine oxidase A (MAOA) genotype. Data were drawn from a longitudinal study of a population-based cohort, followed for three decades. In women, low expression of MAOA (MAOA-L) was related significantly to greater happiness (0.261 SD increase with one L-allele, 0.522 SD with two L-alleles, P=0.002) after adjusting for the potential effects of age, education, household income, marital status, employment status, mental disorder, physical health, relationship quality, religiosity, abuse history, recent negative life events and self-esteem use in linear regression models. In contrast, no such association was found in men. This new finding may help explain the gender difference on happiness and provide a link between MAOA and human happiness.

Concepts: Evolution, DNA, Happiness, Linear regression, Biology, Gene, Monoamine oxidase, Genetics

29

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

Concepts: Tyrosine, Monoamine oxidase, L-DOPA, Neurotransmitter, Norepinephrine, Epinephrine, Catecholamine, Dopamine

29

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.Molecular Psychiatry advance online publication, 15 January 2013; doi:10.1038/mp.2012.172.

Concepts: Cerebrum, Psychology, Fear, Cognitive behavioral therapy, DNA, Monoamine oxidase, Genetics, Gene