Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing

Rationale Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning. Objectives The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for. Results Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities. Conclusions The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.     

血小板RNA与肿瘤

血小板是人体中重要的无核血细胞,生理状态下主要发挥止血和促进伤口愈合的作用。此外,血小板也参与了多种病理过程,主要包括炎症、血管生成、组织再生以及肿瘤的恶性发展等。目前,大量研究显示血小板在肿瘤发生发展中发挥着极其重要的作用,并且参与了肿瘤发生发展的多个过程。最新的研究证明肿瘤微环境中血小板RNA水平发生明显改变并且影响着肿瘤的发展进程。该文综述了近几年报道的在肿瘤微环境中肿瘤细胞对血小板RNA影响及其可能产生的病理效应的相关研究。为临床肿瘤检测以及基于RNA进行血小板与肿瘤之间交互作用的研究提供一定指导。     

Molecular basis of human MAO A and B

Monoamine oxidase A and B (MAO A and B) catalyze the oxidative deamination of a number of biogenic and xenobiotic amines with different substrate and inhibitor specificities. Recently, cDNA clones that encode the human liver MAO A and B have been isolated. Comparison of the deduced amino acid sequences shows that they are 70% homologous and they appear to be derived from separate genes. Expression of functional enzymes by transient transfection of the cDNAs provide unequivocal evidence that the different catalytic activities of MAO A and B reside in their primary amino acid sequences. These two genes located on the X chromosome, Xp11.23, are deleted in some patients with Norrie disease. The possible role or the linkage of MAO genes to a number of diseases can now be investigated.     

Chronic MAO A and MAO B inhibition decreases the 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase

The effect of chronic administration of various monoamine oxidase (MAO) inhibitors on the ability of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to inhibit forskolin-stimulated adenylate cyclase activity was studied. Groups of 12 rats were given either saline, (E)-beta-fluoromethylene-m-tyrosine (MDL 72394 0.25 mg/kg p.o.), clorgyline (1 mg/kg p.o.), selegiline (1 mg/kg p.o.) or tranylcypromine (5 mg/kg p.o.) once a day for 21 days. Biochemical determinations were made 72 h after the final dose. MDL 72394 and tranylcypromine produced a nonselective inhibition of MAO but clorgyline and selegiline selectively inhibited MAO A and MAO B respectively. All treatments that inhibited MAO A also increased tissue levels of 5-HT. Chronic treatment with MDL 72394, clorgyline or tranylcypromine reduced the ability of 8-OH-DPAT to inhibit forskolin-stimulated adenylate cyclase activity. These data suggest that chronic nonselective and chronic MAO A inhibition causes a down-regulation of the 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase activity.     

Platelet receptors

Well-understood functions for "traditional" platelet receptors are described, but "newer" receptors are equally discussed. Receptors are described biochemically (structure, ligand(s), protein partners, and function) and whenever possible, their clinical importance (mutations, polymorphisms, syndrome) are highlighted.     

Platelet signaling

This chapter summarizes current ideas about the intracellular signaling that drives platelet responses to vascular injury. After a brief overview of platelet activation intended to place the signaling pathways into context, the first section considers the early events of platelet activation leading up to integrin activation and platelet aggregation. The focus is on the G protein-mediated events utilized by agonists such as thrombin and ADP, and the tyrosine kinase-based signaling triggered by collagen. The second section considers the events that occur after integrin engagement, some of which are dependent on close physical contact between platelets. A third section addresses the regulatory events that help to avoid unprovoked or excessive platelet activation, after which the final section briefly considers individual variations in platelet reactivity and the role of platelet signaling in the innate immune response and embryonic development.     

Influence of MAO A and MAO B on the inactivation of noradrenaline in the saphenous vein of the dog

Specific inhibitors of MAO A (clorgyline 0.1 mumol/l) and of MAO B [(-)deprenyl 10 mumol/l] were used in dog saphenous vein strips in order to study the relative influence of the two types of MAO on: 1. Termination of contractile response to exogenous noradrenaline (NA); 2. Metabolism and accumulation of exogenous (3H)-NA; 3. Metabolism of 3H-NA released by electrical stimulation. To study the termination of contractile response to exogenous NA, the oil immersion technique was used to determine the time for half-relaxation. The experiments were performed on strips with or without treatment with cocaine 10 mumol/l (to inhibit neuronal uptake) plus U-0521 100 mumol/l (to inhibit catechol-O-methyl transferase) before and after exposure to MAO inhibitors. Clorgyline, but not (-)deprenyl enhanced significantly the time for half-relaxation of the strips, whether cocaine was present or not. To study the metabolism and accumulation of exogenous 3H-NA, the strips were incubated (with or without preincubation with cocaine) with 3H-NA 0.23 mumol/l and 2.3 mumol/l in the presence and in the absence of MAO inhibitors. The formation of deaminated metabolites was significantly reduced by clorgyline, but not by deprenyl. To study the metabolism of 3H-NA released by electrical stimulation, the strips were incubated with 3H-NA 1.4 mumol/l. In the presence of cocaine and U-0521, field stimulation was applied during two periods of 5 min (10 Hz, 100 V, 2 ms), in the absence or presence of MAO inhibitors. Under these experimental conditions clorgyline, but not deprenyl, abolished DOPEG formation, without affecting the other metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

感冒通片中胆红素的HPLC测定

采用ＨＰＬＣ法，μ－ＢｏｎｄａｐａｋＣ１８柱，以氯仿－甲醇－Ｎ，Ｎ－二甲基甲酰胺（５４∶４０∶６）为流动相，４５０ｎｍ为检测波长，测定感冒通片中胆红素的含量。平均回收率为９９．７％，ＲＳＤ为０．１％。方法简单、快速、准确     

Irreversible Inhibition of Rat Liver Mitochondrial MAO A and MAO B by Enantiomers of Deprenyl and α-Methylpargyline

Using rat liver mitochondrial monoamine oxidase (MAO) A and MAO B, the possible influence of stereochemical factors upon the irreversible inhibition by propargylamine derivatives has been studied using the enantiomers of deprenyl and of α-methylpargyline. Whether studying the inhibition of MAO A or MAO B, little difference was found among enantiomeric pairs in the first-order rate constant (k₂) for formation of the enzyme inhibitor adduct. Similarly, and with the exception of (S)-d -(+)-deprenyl (k₂ = 0 or an extremely low value at MAO A), the computed value of k₂ for the individual enantiomers showed little variation between MAO A and MAO B. These results suggest that inhibitor selectivity towards a particular form of the enzyme is determined predominantly at the competitive phase of the inhibition.     

Short-acting novel MAO inhibitors: In vitro evidence for the reversibility of MAO inhibition by moclobemide and Ro 16-6491

Summary The inhibition of monoamine oxidase (MAO) in rat liver and brain by the short-acting MAO-A inhibitors moclobemide (Ro 11-1163 = p-chloro-N-[2-morpholinoethyl]benzamide) and brofaremine and by the short-acting MAO-13 inhibitors Ro 16-6491 (N-[2-aminoethyl]-p-chlorobenzamide) and almoxatone, administered p. o. at roughly equieffective doses 2 h before decapitation, was investigated for its reversibility under various in vitro conditions. MAO A activity in liver homogenates, inhibited by moclobemide (300 mol/kg) to approx. 15% of control, time dependently recovered during 0.5 to 2 h of incubation at 37°C, irrespective of whether the homogenates were prepared and incubated in distilled water or Krebs-Ringer buffer (KRB). Dialysis of such homogenates for 4 h in distilled water at 37°C (but not at 13°C) led to a complete return of the MAO activity. In liver homogenates from rats pretreated with brofaremine (30 mol/kg), dialysis for 4 h at 37°C against distilled water caused only little recovery of the MAO activity. Likewise, MAO-B inhibited by Ro 16–6491 (30 mol/kg) to approx. 4% of control returned to almost control activity after 4 h of dialysis at 37°C, while inhibition induced by almoxatone (30 mol/kg) was little or not reversed at all. In brain homogenates prepared in, and dialysed against, distilled water or KRB at 37°C (but not at 13°C), MAO-A inhibited by moclobemide (100–300 mol/kg) to approx. 15% of control, partially (KRB) or almost completely (dist. water) returned to control activity after 4 h of dialysis. From rats pretreated with Ro 16–6491 (30 mol/kg), MAO-B in brain homogenates prepared in KRB was reduced to 12% of control and returned to control value upon dialysis for 4 h in KRB at 37°C; in homogenates prepared in H₂O, MAO-B was reduced to only 60% of control and completely recovered by dialysis against dest. water even at 13°C. In all of these conditions, recovery of the enzyme activity was small after brofaremine and almoxatone. Analogous results were obtained with brain slices (0.2 × 0.2 × 1.5 mm) in KRB at 37°C, whereby time dependent recovery of MAO activity during incubation was achieved, and superfusion was somewhat more effective than incubation in restoring enzyme activity. In the experiments with incubated or superfused brain slices, inhibition of MAO-A and -B by the irreversible inhibitors clorgyline and selegiline (l-deprenyl), resp., could not be reversed at all. Tyramine (0.3 mmol/l) clearly enhanced the recovery of MAO-A in KRB-prepared liver homogenates and brain slices of moclobemide-pretreated rats but not in brain slices of brofaremine- and clorgyline-pretreated rats. Thus, the reversibility of MAO inhibition in vitro could be convincingly demonstrated for moclobemide and Ro 16–6491 but not for the other novel, short-acting MAO inhibitors studied. Send offprint requests to H. H. Keller at the above address     

Altered behavior and alcohol tolerance in transgenic mice lacking MAO A: a comparison with effects of MAO A inhibitor clorgyline

The influence of deficiency of monoamine oxidase A (MAO A) gene and the lack of enzyme MAO A on the behavior of transgenic mouse strain (Tg8) was studied. It was shown that MAO-A-lacking mice differed from mice of the wild-type strain C3H/HeJ (C3H) by an attenuated acoustic startle response, prepulse inhibition (PPI) was unchanged. In Tg 8 mice, the exploratory nose-poking in the holeboard test as well as exploratory line crossing in the "light-dark" test were decreased. No effect of MAO A deficiency on locomotor activity was found. No alcohol preference or difference between Tg8 and C3H in ethanol consumption in the free-choice test has been found, although an increase in alcohol tolerance has been demonstrated. Ethanol-induced (0.3 g/100 g ip) sleep latency was longer, duration of sleep was shorter and ethanol hypothermia was reduced in MAO-A-lacking mice. Comparison of effects of MAO A knockout with those of irreversible MAO A inhibitor clorgyline (5 and 10 mg/kg ip) on C3H mice showed a similar reducing effect on ethanol-induced sleep, but potentiated ethanol-induced hypothermia. Clorgyline administration provoked a tendency to decrease of exploratory activity in the nose-poking test and decreased the frequency of exploratory rearings in the light-dark test. Clorgyline (5 and 10 mg/kg) did not affect the acoustic startle response, but a dose of 5 mg/kg diminished PPI. Therefore, Tg8 mice exhibited a decreased startle response and exploratory activity and an increased tolerance to ethanol. A similar increase in tolerance to ethanol-induced sleep and a tendency to decrease exploratory behavior were displayed by clorgyline. Other effects on behavior were different, suggesting the influence of long-lasting action of MAO A knockout and the involvement of a compensatory mechanism in Tg8 mice.     

MAO types in guinea pig liver mitochondria

MAO of guinea pig liver mitochondria actively deaminated dopamine, tyramine, serotonin and 5-methoxy-tryptamine, while tryptamine, 5-methyl-tryptamine and 7-methyl-tryptamine were moderately deaminated. Very little deamination occurred when benzylamine. noradrenaline and β-phenylethylamine were used as substrates. The in vitro inhibition patterns of MAO of guinea pig liver mitochondria by some selective inhibitors were investigated in the presence of tyramine, tryptamine and serotonin. Tryptamine oxidation showed biphasic inhibition pattern with harmaline, clorgyline and Lilly 51641, while the inhibition curves in the presence of pargyline and deprenyl were sigmoidal. The inhibition curves for tyramine oxidation were biphasic with all the inhibitors except pargyline. Serotonin-MAO inhibition curves, on the other hand, were sigmoidal with all the inhibitors except Lilly 51641. Thermal treatment of guinea pig liver mitochondria produced rapid inactivation of serotonin and tryptamine oxidizing activity, while benzylamine oxidizing activity was found to be most thermostable.