Reduced brain monoamine synthesis by systemic treatment with terbutaline,a β2-receptor agonist

Summary The effects of acutely (5 mg/kg s.c.) or subchronically (2.5 mg/kg s.c., twice daily, 4 days) administered terbutaline, a ₂-receptor agonist, on thein vivo rate of tryptophan and tyrosine hydroxylation in various rat brain parts were studied. The accumulation of 5-hydroxytryptophan (5-HTP) during 30 min following treatment with NSD 1015, 100 mg/kg i.p., an inhibitor of L-aromatic amino acid decarboxylase, appeared reduced in several brain parts by the terbutaline treatments, the effect being significant in the limbic forebrain and the hemispheres after subchronic administration. This treatment also reduced the simultaneously measured accumulation of 3, 4-dihydroxyphenylalanine (DOPA) in the same brain parts as well as in corpus striatum, where the effect was seen also after acutely administered terbutaline. The concentration of tryptophan in the various brain parts was not significantly affected by the terbutaline treatments and the tyrosine levels were only reduced in some brain parts (the hemispheres and the brain stem). The central effects obtained by terbutaline treatment may be mediated indirectlyvia peripheral inputs toe.g. the monoamine carrying neurons and/orvia putative changes in cerebral blood flow.     

Is monoamine oxidase inhibitor induced myoclonus serotoninergically mediated?

Summary In the present study a single case observation of myoclonus during sleep-wave transition was monitored in a depressed patient treated with the monoamine oxidase inhibitor, phenelzine. The myoclonus had a rhythm of 1 c/second and lasted for two years, the duration of phenelzine treatment. Myoclonus appeared neither during wakefulness nor during sleep, but at wake-sleep-wake transitions. This switch myoclonus was associated with phasic muscle hyperactivity during REM sleep.Methysergide a 5-HT suppressor, decreased the switch myoclonus frequency and the REM muscle hyperactivity, indicating serotoninergic involvement in the mechanism of phenelzine induced myoclonus.     

The effect of β-alanine on motor behaviour,body temperature and cerebral monoamine metabolism in rat

Summary Intracerebroventricular (ICV) injection of-alanine produced a decrease in rectal temperature, inhibition of exploratory behaviour and motility, and changes in the metabolism of cerebral monoamines. Dopa and 5-HTP accumulation after inhibition of L-aromatic amino acid decarboxylase, NSD 1015 (3-hydroxybencylhydrazine HCl, 100mg/kg i.p.) was found to be significantly increased in all the dissected cerebral regions of animals treated with-alanine, as compared to the controls. Levels of tyrosine and tryptophan did not show any significant change. Endogenous levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), did not change. After inhibition of the catecholamines synthesis with-methyltyrosine (-MT), dopamine depletion was retarded and noradrenaline accelerated, but without reaching statistical significance. After intraperitoneal (i.p.) injection of-alanine, significant changes in motor behaviour were found. Body temperature and metabolism of brain catecholamine were unchanged. This lack of effect could be explained by poor penetration through the blood-brain barrier.     

β-Carbolines as selective monoamine oxidase inhibitors:In vivo implications

Summary The inhibitory action of a range of-carbolines on human and rat monoamine oxidase (MAO) A and B has been studied. Concentrations of 5-hydroxytryptamine and phenylethylamine, approximately at their K_m values, were used as substrates for MAO A and B respectively. A wide variation in selectivity was found, with harmaline being 10,000 times more potent an inhibitor of A than B whereas, using tetrahydro--carboline and harmane, the difference was nearer to ten-fold. Of the carbolines which have been found endogenously, tetrahydro--carboline, 6-methoxytetrahydro--carboline and harmane are all sufficiently potent inhibitors of human MAO A, with I₅₀ values of 5×10^–6, 10^–6, 5×10^–7M respectively, for this property to be of possible physiological significance. Harmane, with an I₅₀ of 5×10^–6M, might also play a role as an inhibitor of MAO B.     

Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Phentermine produces a spectrum of concentration-dependent biochemical effects. It interacts with NE transporters at 0.1 microM, DA transporters at about 1 microM, 5-HT transporters at 15 microM and MAO-A at about 100 microM. When administered at typical anorectic doses, phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting MAO-A. Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5-HT, since platelet MAO-B does not metabolize platelet 5-HT, and since amphetamine-type drugs are even weaker inhibitors of MAO-B than MAO-A. Clinical studies in humans have shown that amphetamine, which is a more potent inhibitor of MAO-A than phentermine, does not inhibit MAO-A at therapeutic doses. Neither phentermine alone, fluoxetine alone or their combined use have been associated with cardiac valvulopathy, and clinical experience has shown their combined use to be free of significant adverse effects. Viewed collectively, there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses.     

Platelet monoamine oxidase activity in subjects tested for Huntington’s disease gene mutation

Summary. Monoamine oxidase activity (MAO) has been related to neuronal damage, since the oxidative deamination of biogenic amines produces free radicals that may enhance oxidative stress. Elevated enzyme activities in brain (MAO-A and MAO-B forms) and in platelets (MAO-B form) have been reported in several degenerative diseases, indicating that MAO activity may be involved in the disease progression. We estimated platelet MAO activity in a group of 59 patients (34 males) with HD, 20 subjects (7 males) at risk, and 29 (14 males) healthy subjects with positive family history for HD, categorized according to clinical features and the number of CAG repeat units (CAG-RN) at the Huntington gene. A group of 64 subjects (36 males) with negative family history for HD served as controls. In contrast to some previous studies, platelet MAO activities in both male and female patients (CAG-RN 40 to 62) with overt symptomatology, were not different compared to same sex control subjects. Subjects at risk (CAG-RN 39 to 52), though, showed significantly lower activities compared to same sex patients or controls. MAO activities seem to increase with disease progression, and tend to be higher in patients with dementia. The increases may be an epiphenomenon of disease pathology, but the possibility that an increase in the expression of the enzyme precedes the onset of the disease and contributes to enhanced oxidative stress should be considered in future longitudinal studies as a possible mechanism that accelerates disease progression.     

Platelet monoamine oxidase in healthy subjects: The “biochemical high-risk paradigm” revisited

Summary Activity of platelet monoamine oxidase (MAO) has repeatedly been reported to be associated with various forms of psychopathology. This investigation was designed to reexamine the biochemical high-risk paradigm developed by Buchsbaum et al. (1976). In 383 healthy students (193 males, 190 females) platelet MAO activity was measured. The 35 students with the lowest and 37 with the highest enzyme activities were then examined with three personality tests (16 PF of Cattell, Freiburger Persönlichkeitsinventar, Eysenck Personality Questionnaire). Furthermore, biographic data with respect to psychosocial problems were explored. There were no consistent differences between subjects with low or high platelet MAO. Therefore, we could not confirm any correlation between psychopathology and platelet MAO in this study.Supported by the Deutsche Forschungsgemeinschaft     

Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development — but not during adult life — is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke–induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke.     

Computational investigation on the structure–activity relationship of the biradical mechanism for monoamine oxidase

Although a considerable amount of mechanistic data has accumulated in literature, the detailed mechanism for amine oxidation by monoamine oxidase is still controversial. The single electron transfer mechanism (SET) has been widely discussed, but not completely understood yet. In the present study, the modified SET mechanism, proposed by Silverman et al., was explored by quantum chemical calculations. The ONIOM method was applied with UDFT/B3LYP/6-31 + G(d,p) for the higher layer and with UHF/6-31G(d) for the lower layer. Isoalloxazin heterocyclic ring and benzylamine were employed in the calculations to represent flavin and the substrate, respectively. The substituents CH₃, OH, OCH₃, H, F, Cl, Br, CF₃ and NO₂ were incorporated at the para position of benzylamine to explore structure–activity relationships. The structures of the reactant complex, transition state and product complex were fully optimized. Activation energies and rate constants of all the reactions were calculated. The results obtained from the linear regression analysis showed that electron-donating groups at the para position of benzylamine increase the reaction rate. A linear but inverse correlation between the log of the calculated rate constants (log k) and the electronic parameter of the substituent was observed (R = 0.93). In accordance with this result, a relatively weak inverse correlation between the calculated log k and the experimental log k was obtained (R = 0.78). The results are contrary to the previous kinetic experiments and the computational study on the effect of p-substituents in the flavin reduction of MAO A by p-substituted benzylamine analogs. Therefore, they present negative evidence for the modeled biradical mechanism.     

Sleep timing,chronotype, mood,and behavior at an Arctic latitude (69°N)

ObjectiveDaylight is an important zeitgeber for entraining the circadian rhythm to a 24 h clock cycle, especially within the Polar circle, which has long Polar nights several months each year. Phase delays in sleep timing may occur, but the mean shift is normally small. However, the individual variation in phase shifts is large, implicating moderating factors. Here we examined the role of several self-regulatory variables (mood and fatigue, behavioral habits, and psychological self-regulation) as moderators of seasonality in sleep timing and chronotype.MethodsA sample of 162 young adults (76% females; mean age: females 23.4 years, males 24.3 years) participated in a prospective study across three seasons (September, December, March) in Tromsø/Norway at 69°39′N. Sleep diary and sleep/health-related questionnaire data were collected at each time-point.ResultsSleep timing and chronotype were delayed during the dark period (December) compared with brighter photoperiods (September and March). Comparable effects were observed for insomnia, fatigue, mood (depression and anxiety), subjective health complaints, physical activity, and school-related stress. Most importantly, depression and fatigue moderated the degree of seasonal shifting in sleep timing, whereas the other self-regulation indicators did not (ie eating habits, physical activity, and psychological self-regulation).ConclusionSeasonality in sleep timing and chronotype was confirmed, and it seems that depressive symptoms during the dark period exacerbate phase-shifting problems for people living in sub-Arctic regions.     

Variations in the monoamine oxidase-inhibitory activity (“tribulin?”) in pig's urine

Summary Sandler and his colleagues (see Sandler, 1982) have demonstrated the presence of an endogenous inhibitor of the enzyme monoamine oxidase (MAO) and of benzodiazepine receptor binding in the urine and blood plasma of man and rat. The concentrations of this material increased under stress conditions and it has been named tribulin. In the present experiments MAO-inhibitory activity was found in extracts of urine and plasma samples of domestic pigs. Evidence was obtained that the inhibitory activity was higher when pigs experienced slight discomfort. Thus it appears that pigs produce a substance similar to tribulin. It may become possible to use such MAO-inhibitory activity as an indicator in the assessment of interaction with the environment in pig husbandry.     

分子·细胞生物学常用词汇(M部,N部,O部,P部)

ＭＡＰｋｉｎａｓｅ/ＭＡＰ激酶　可被多种生长因子刺激细胞所激活的蛋白激酶 ,通过使特异靶蛋白磷酸化来介导细胞反应。ｍｉｔｏｇｅｎ/丝裂原　能促进细胞增殖的任何胞外物质 ,如生长因子。 ｍｏｂｉｌｅＤＮＡｅｌｅｍｅｎｔ/可动ＤＮＡ成分　在一个种属的每个个体 ,其染色体位点不尽相同的那些ＤＮＡ序列。ｍｏｔｉｆ/基序　一种蛋白质的结构单位 ,具有特定的三维结构 ,见于各种蛋白 ,常常与特殊功能相关联。ｍｏｔｏｒｐｒｏｔｅｉｎ/动力蛋白　 一类特殊酶的成员如肌球蛋白、动力蛋白及驱动蛋白。它利用ＡＴＰ水解的能量 ,沿微丝 (肌…     

5-hydroxytryptamine actions in adipocytes: involvement of monoamine oxidase-dependent oxidation and subsequent PPARγ activation

Serotonin (5-HT) is a brain neurotransmitter instrumental for the antidepressant action of selective inhibitors of serotonin reuptake (SSRIs) while it also plays important roles in peripheral organs. Recently, the 5-HT oxidation products, 5-hydroxyindoleacetate and 5-methoxy-indoleacetate, have been shown to bind to peroxisome proliferator-activated receptor γ (PPARγ) and to enhance lipid accumulation in preadipocytes. Since we already reported that adipocytes exhibit elevated monoamine oxidase (MAO) and primary amine oxidase activities, we verified how adipocytes readily oxidize 5-HT, with the objective to determine whether such oxidation promotes PPARγ activation and lipid storage. To this aim, serotonin was tested on cultured 3T3 F442A preadipocytes and on human adipocytes. Results showed that 5-HT was oxidized by MAO in both models. Daily treatment of 3T3 F442A preadipocytes for 8 days with 100–500 μM 5-HT promoted triglyceride accumulation and emergence of adipogenesis markers. At 250 μM, 5-HT alone reproduced half of 50 nM insulin-induced adipogenesis, and exhibited an additive differentiating effect when combined with insulin. Moreover, the 5-HT-induced expression of PPARγ-responsive genes (PEPCK, aP2/FABP4) was blocked by GW 9662, a PPARγ-inhibitor, or by pargyline, a MAO-inhibitor. In human fat cells, 6-h exposure to 100 μM 5-HT increased PEPCK expression as did the PPARγ-agonist rosiglitazone. Since hydrogen peroxide, another amine oxidation product, did not reproduce such enhancement, we propose that serotonin can promote PPARγ activation in fat cells, via the indoleacetate produced during MAO-dependent oxidation. Such pathway could be involved in the adverse effects of several antidepressant SSRIs on body weight gain.     

Interventional effect of electroacupuncture combined with medicine on monoamine neurotransmitters in hypothalamus of rats with ulcerative colitis

BACKGROUND: Ulcerative colitis (UC) is conventionally treated with sulfasalazine and other aminosalicylic acids. The symptoms of UC can be rapidly controlled, but high recurrence, severe adverse reactions and other shortages exist commonly. Whether electroacupuncture combined with medicine can make up these shortages remains unclear. OBJECTIVE: This study was to observe the regulatory effect of electroacupuncture combined with medicine on monoamine neurotransmitter in hypothalamus of rats with ulcerative colitis, and to analyze the pathogenesis of UC and the action pathway of electroacupuncture combined with medicine. DESIGN: A randomized controlled observation. SETTING: Shanghai Institute of Acupuncture and Meridian. MATERIALS: Thirty involved male SD rats of clean grade, weighing （200±20）g, were provided by the Experimental Animal Center, Shanghai University of Traditional Chinese Medicine. Sulfasalazine was produced in the Shanghai Sanwei Pharmaceutical Co., Ltd [certification No. (1995)002083]. METHODS: This study was carried out in the State Laboratory (grade 3) for Acupuncture and Immunology, Shanghai Institute of Acupuncture and Meridian. The involved 30 rats were randomized into 5 groups: normal group, model group, electroacupuncture group, medicine group and electroacupuncture combined with medicine group, with 6 rats in each group. Rats in the latter 4 groups were prepared into models of UC. In the electroacupuncture group, Zusanli(shuang) point was selected. Electro-acupuncture apparatus (G6805Ⅱ type) was connected to the point and used to stimulate it with continuous wave, frequency of 2 Hz, electrical intensity 4 mA, 20 minutes a day, for 14 days successively. In the medicine group, rats were intragastrically administrated with sulfasalazine, twice a day, 3 mL once, for 14 days successively. In the electroacupuncture combined with medicine group, rats were treated with electroacupuncture and medicine simultaneously as described in the previous two groups. Rats in the model group and normal control group were untouched except for being fixed. MAIN OUTCOME MEASURES: The levels of noradrenaline acid tartrate (NE), 3-methoxy-4 hydroxyphenylglycol (MHPG), dopamine hydrochloride (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxytryptamine (5-HT) hydrochloride, homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) of rats in each group were detected by high-performance liquid chromatography (HPLC)-electrochemical method. RESULTS: All the 30 involved rats entered into the stage of final analysis. ①Detection of NE and MHPG levels: After treatment, NE level in the hypothalamus of rats was significantly higher in the electroacupuncture combined with medicine group, electroacupuncture group and medicine group was all significantly higher than that in the model group, respectively (P < 0.01). After treatment, MHPG level in the metabolite of NE was very significantly higher in the electroacupuncture group than in the medicine group (P < 0.01). ②Detection of DA and DOPAC levels: After treatment, DA level in the hypothalamus of rats was very significantly higher in the medicine group than in the model group (P < 0.01). ③Detection of 5-HT, HVA and 5-HIAA levels: After treatment, 5-HIAA level in the hypothalamus of rats was significantly higher in the medicine group than in the model group (P < 0.05). CONCLUSION: The abnormal synthesis and metabolism of monoamine neurotransmitter in the central nervous system is one of pathogenesis of UC. Electroacupuncture combined with medicine might reach its goal of treatment by regulating the monoamine neurotransmitter disorder in the hypothalamus of rats with UC.     

Vesicular monoamine transporter 2 mRNA levels are reduced in platelets from patients with Parkinson’s disease

Despite advances in neuroimaging, the diagnosis of idiopathic Parkinson’s disease (PD) remains clinical. The identification of biological markers for an early diagnosis is of great interest to start a neuroprotective therapy aimed at slowing, blocking or reversing the disease progression. Vesicular monoamine transporter 2 (VMAT2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and release. Thus, VMAT2 impairment can regulate intra- and extracellular dopamine levels, influencing oxidative stress and neuronal death. Because in vivo imaging studies have demonstrated a VMAT2 reduction in PD patients greater than would be explained by neuronal loss alone, as an exploratory study we assessed VMAT2 mRNA and protein levels in platelets from 39 PD patients, 39 healthy subjects and 10 patients with vascular parkinsonism (VP) to identify a possible peripheral biomarker for PD. A significant reduction (p < 0.05) of VMAT2 mRNA levels was demonstrated in PD patients versus healthy controls. Patients with VP showed VMAT2 mRNA levels similar to controls. No difference in VMAT2 mRNA levels was found in untreated versus treated patients. No correlation was observed between mRNA levels and demographic or clinical characteristics. Furthermore, eight SNPs tagging the VMAT2 gene did not show effects on VMAT2 mRNA levels. Western blot analysis did not allow the quantification of VMAT2 protein expression in blood platelets. Although further studies in a greater number of cases are needed to confirm our data, the reduction in VMAT2 mRNA in platelets from PD patients suggests the existence of a systemic impairment of this transporter possibly contributing to PD pathology.     

Untersuchungen zum Nüchternblutzucker von endogen Depressiven,Schizophrenen und Neurotikern

Zusammenfassung Endogen Depressive, Schizophrene und Neurotiker werden hinsichtlich ihres Nüchternblutzuckers miteinander verglichen. Die Untersuchung ergibt bei endogen Depressiven gegenüber Schizophrenen und Neurotikern eine signifikante Erhöhung des durchschnittlichen Nüchternblutzuckers. Der Befund wird als Feinsymptom der Glukosetoleranzminderung bei endogener Depression interpretiert. Zusammenhänge bestehen weder mit dem Geschlecht, noch dem Körpergewicht im Verhältnis zur Körpergröße, noch dem Lebensbzw. Aufnahmealter. Zur Erklärung des Befundes werden verschiedene Hypothesen diskutiert.     

Therapeutic Efficacy of the N,N′ Bis-(2-Mercaptoethyl) Isophthalamide Chelator for Methylmercury Intoxication in Caenorhabditis elegans

Neurotoxicity Research - Methylmercury (MeHg) is a global pollutant and potent neurotoxin. In humans, MeHg damages the central nervous system (CNS), causing irreversible neuronal shrinkage, and...