次黄嘌呤对单胺氧化酶的抑制作用

实验证明给小鼠po次黄嘌呤25～500 mg/kg时,对肝和脑中单胺氧化酶B(MAOB)活性的抑制作用与剂量成明显的量—效关系,对MAO-A活性的抑制较弱,且无明显的量—效关系。给小鼠一次po次黄嘌呤500 mg/kg,于给药后16h,对MAO抑制作用最明显。sc时,对肝中MAO活性抑制也以给药后16 h最明显,但对脑中MAO活性抑制不明显。离体实验证明,次黄嘌呤对MAO-B的抑制为竞争性,对MAO-A则为混合型抑制。     

对—羟基苯甲醛和对—羟基苯甲酸对单胺氧化酶活性的影响

小鼠灌服对一羟基苯甲醛(PHBAD)和对一羟基苯甲酸(PHBZA)能明显抑制脑和肝组织的单胺氧化酶(MAO)活性,且对MAO—B的抑制作用强于MAO—A。PHBAD(200～400mg·kg~(-1)对小鼠脑MAO—B抑制作用强于PHBZA。体外实验证明,二者对MAO—B的抑制作用随浓度增加而明显增强。另外,PHBAD对MAO—B呈竞争型抑制;对MAO—A呈混合型抑制;而PHBZA对MAO-B、MAO—A均呈混合型抑制。     

Cumulative effects of irreversible MAO inhibitors in vivo

The effects of repeated treatment with clorgyline, pargyline, deprenyl and tranylcypromine on MAO activity in rat brain and liver were investigated. MAO was measured with the substrates serotonin (5HT), phenethylamine (PEA) and, in some cases, t brain tissue after single and repeated administrations of 10 mg/kg s.c. clorgyline or deprenyl were also compared. Single doses of clorgyline (1 and 10 mg/kg s.c.) completely blocked the deamination of 5-HT. PEA deamination gradually decreased during the 14-day treatment. Pargyline in a dose of 0.3 mg/kg s.c. reduced both 5-HT and PEA deamination progressively over the same period. In the course of repeated treatment the effects of clorgyline and deprenyl on 5-HT and PEA deamination increased in intensity, by a factor of about 10 in the brain and about 3 in the liver. The potentiation of the effect of tranylcypromine was less marked (brain: × 4; liver: × 2). The rates of recovery of MAO activity were not greater after repeated than after single administrations of high doses of clorgyline and deprenyl, suggesting that the withdrawal of the drugs is not followed by a rebound phenomenon. Our results indicate that repeated treatment with suitable doses of clorgyline or deprenyl leads to specific reduction of either MAO A or B activity in brain, without producing any appreciable effect in the liver.     

Effect of lignocaine on monoamine oxidase activity of brain and liver

In vivo administration of a single dose (100-150 mg/kg, i.p.) of lignocaine produces no change in MAO activity, while long-term treatment (50 mg/kg/day for 15 and 30 consecutive days, i.p.) produces a slight but appreciable inhibition of MAO activity with tyramine or serotonin but not with benzylamine as substrate in both rat brain and liver mitochondria. Lignocaine (2-20 mM) inhibits (in vitro) both brain and liver mitochondrial MAO activity, using tyramine, serotonin and benzylamine as substrates, in a concentration-dependent manner. Furthermore, lignocaine produces a marked in vitro inhibition of serotonin and tyramine oxidation in MAO-A and not in MAO-B preparation of rat brain. Ackermann-Potter plots of MAO indicate that lignocaine-induced inhibition of MAO activity is reversible in nature. Lineweaver-Burk plots show that lignocaine (2-10 mM) produces a significant increase in Km and decrease in Vmax of MAO for tyramine and serotonin in both brain and liver. Similarly Km and Vmax values are changed using benzylamine as substrate in the presence of relatively higher concentrations of lignocaine (5-20 mM). These results suggest that lignocaine-induced inhibition of mitochondrial membrane-bound MAO activity of both neuronal and non-neuronal tissues is associated with its conformational change.     

Allylamine cardiotoxicity: III. Protection by semicarbazide and in vivo derangements of monoamine oxidase

We hypothesized that inhibition of monoamine oxidase (MAO) might protect the myocardium from the necrosis and fibrosis induced by allylamine consumption; therefore, we gave rats several MAO inhibitors simultaneously with allylamine (10.7 mM) in drinking water for 3 weeks. Semicarbazide (1.4 mM) prevented histopathologic cardiac lesions, while hydroxylamine (2.2 mM) decreased their severity. Other inhibitors tested — tranylcypromine (20 μM) and pargyline (15 μM) — did not decrease lesion incidence or severity. Weight gain and fluid consumption varied depending on treatment: these parameters resembled control values in rats protected by semicarbazide and in rats consuming tranylcypromine, but were decreased in rats consuming other inhibitors or only allylamine. We repeated the experiment, measuring MAO activity (toward 3 substrates) of brain, liver, and heart homogenate in rats given only the inhibitors, only allylamine, or allylamine combined with the inhbitors. Brain and liver MAO activities were not greatly affected by semicarbazide or hydrodxyalmine but were decreased as much as 60% by tranylcypromine and by pargyline. Cardiac MAO was significantly inhibited only by tranylcypromine. Allylamine also inhibited brain and liver MAO, but caused by anomalous, marked increase in cardiac MAO. Further study showed that this high cardiac MAO activity followed an initial decrease during the first day of the experiment, became manifest after 10 days, and was directly proportional to the histopathologic severity of cardiac lesions at 21 days. In rats given allylamine plus the MAO inhibitors, brain and liver MAO activity generally decreased. Cardiac MAO activity, however, increased in rats given allylamine plus tranylcypromine or pargyline, but did not differ from control activity in hearts protected from allylamine-induced lesions by semicarbazide or hydroxylamine. A single dose of allylamine (50–150 mg/kg body wt) given by gavage induced dose-dependent inhibition of MAO activity toward β-phenylethylamine in all 3 organs at 24 h. We conclude that the mechanism of protection from allylamine-induced cardiac injury is not MAO inhibition. Our studies, however, show marked systemic aberrations in MAO activity during allylamine intoxication, and complex cardiac MAO changes which probably results from the myocellular damage.     

LACK OF EFFECT OF CHLORAMPHENICOL ON MONOAMINE, DIAMINE AND PLASMA AMINE OXIDASE ACTIVITIES

Chloramphenicol treatment in rabbits (60 mg/kg i.m. for 5 days) did not affect significantly (P greater than 0.1) the activities of monoamine oxidase (MAO) or diamine oxidase (DAO) in liver, heart or brain. Plasma amine oxidase (PAO) was not significantly inhibited (P greater than 0.1) in goats treated with chloramphenicol (60 mg/kg i.m. for 5 days). Chloramphenicol (2 X 10(-3) mol/l) preincubated with rabbit hepatic MAO had no significant effect (P greater than 0.1) on the enzyme activity.     

SOME CARDIOVASCULAR EFFECTS OF MONOAMINE OXIDASE INHIBITORS IN UNANAESTHETIZED RATS

The effects of four monoamine oxidase (MAO) inhibitors on the blood pressure of conscious normotensive and DOC-salt hypertensive rats were measured. Harmaline (20 mg/kg p.o.), pargyline (100 mg/kg p.o.) and tranylcypromine (10 mg/kg p.o.) all lowered blood pressure significantly in both normotensive and hypertensive rats whereas methylaplysinopsin (10 mg/kg p.o.) had no effect on blood pressure. The effects of these MAO inhibitors on blood pressure responses to serotonin, tyramine and beta-phenylethylamine were determined in conscious normotensive rats. Pargyline and tranylcypromine shifted the dose-response curves for tyramine and beta-phenylethylamine, but not serotonin, to the left, indicating inhibition of type B MAO. Harmaline and methylaplysinopsin shifted the dose-response curves for tyramine and serotonin but not beta-phenylethylamine, to the left, indicating inhibition of type A MAO. Since the four antagonists tested inhibited at least one form of MAO, and yet not all of these MAO inhibitors lowered blood pressure, we suggest that our results are consistent with the view that the hypotensive action of MAO inhibitors is not necessarily related to inhibition of MAO.     

Influence of harmaline on the ability of pargyline to alter catecholamine metabolism in rats

When pargyline hydrochloride (20 mg/kg, i.p.) was injected into rats 48 hr before the measurement of monoamine oxidase (MAO) activity, the oxidation of [¹⁴C]phenylethylamine (type B MAO) and of [¹⁴C]-serotonin (type A MAO) was inhibited. Neither type A nor type B MAO was inhibited 48 hr after the injection of harmaline hydrochloride (30mg/kg, i.p.) a short-acting, reversible, highly selective inhibitor of type A MAO. When harmaline was given just before pargyline, it prevented the inhibition of type A MAO by pargyline but not the inhibition of type B MAO. Pargyline alone elevated epinephrine, norepinephrine, and dopamine concentrations in brain regions and norepinephrine concentration in heart. The concentration of dopamine metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) was decreased. Pretreatment with harmaline prevented all of these effects of pargyline. The findings suggest that inhibition of type A MAO is involved in the inhibition of catecholamine metabolism by pargyline, since harmaline pretreatment did not prevent inhibition of type B MAO and would not be expected to alter any other possible actions of pargyline. These findings support the idea that type A MAO is primarily responsible for the oxidation of epinephrine, norepinephrine, and dopamine in rat brain and of norepinephrine in rat heart.     

Binding of [H]brofaromine to monoamine oxidase A in vivo: displacement by clorgyline and moclobemide

Short duration of action, displaceability by endogenously released monoamines, and absence of cumulation of effect of the selective inhibitor of monoamine oxidase type A (MAO-A), brofaromine (CGP 11305 A), indicate reversibility of its interaction with the enzyme in vivo. However, its in vitro interaction with the enzyme showed features commonly associated with irreversible inhibition. To clarify this issue, the in vivo binding of [³H]brofaromine to MAO-A in areas of the rat brain, and in rat heart and liver was investigated. Specific binding, defined by pretreatment with the irreversible inhibitor, clorgyline, was between 15 and 75% of total binding depending on the tissue and the time elapsed after injection of radioactivity. In brain and heart tissue, unlabelled brofaromine, another reversible inhibitor of MAO-A, moclobemide and clorgyline were able to displace [³H]brofaromine when administered after the labelled compound with ED₅₀s of 1–3 mg/kg p.o., 3mg/kg p.o. and 0.3–1 mg/kg s.c., respectively. In the liver, brofaromine and moclobemide and the inhibitor of drug-metabolizing enzymes, proadifen (SK & F 525 A), were able to significantly inhibit [³H]brofaromine binding. Clorgyline was only marginally effective, suggesting that, in this organ, [³H]brofaromine binds predominantly to such enzymes. In conclusion, the binding of [³H]brofaromine to MAO-A in rat brain and heart in vivo was found to be displaceable by other MAO inhibitors and is therefore reversible. In the liver, the compound bound predominantly to other sites, probably microsomal drug-metabolizing enzymes.     

酶标仪比色法测定单胺氧化酶活性

目的建立用酶标仪比色测定单胺氧化酶A(monoamine oxidase A,MAO A)和MAO B活性的方法。方法以大鼠肝组织匀浆作酶原,分别以血清素(5-HT)和苄胺作为MAO A和MAO B底物,以2,4-二硝基苯肼(DNPH)和氢氧化钠为显色剂,在450 nm处用酶标仪比色测定。结果该方法能快速、灵敏、稳定、选择性地测定MAO活性。结论建立了以酶标仪比色法测定MAO活性的方法用于筛选药物。     

BCEF0083抗单胺氧化酶作用的研究

目的　研究一种白僵菌代谢产物提取物 (BCEF0 0 83)对单胺氧化酶 (MAO)的抑制作用。方法　提取动物脑组织重线粒体应用荧光分光光度计法检测MAO活性 ;采用大、小鼠体内外给药研究BCEF抗MAO作用的量效、时效关系 ,应用林 -贝氏法测定MAOKm值。结果　小鼠BCEF 50 0mg·kg- 1 ,ig给药后 0 5hMAO活性已有抑制 ,2～ 8h活性抑制明显 ,一次给药后 72h抑制作用基本消失 ;小鼠BCEF50 0、40 0、2 0 0、1 0 0、50、2 5mg·kg- 1 ,ig后 2h取脑组织测MAO活性 ,BCEF对MAO活性的抑制呈现一定的量效关系。BCEF体外给药对大鼠脑组织MAO活性的抑制随药物浓度增加而增强 ,BCEF体外给药对MAO A、MAO B抑制的IC50 (95 %可信限 )分别为 1 2 8 88(82 70～ 2 0 0 86)mg·L- 1 、1 84 1 4 (1 56 1 7～ 2 1 7 1 1 )mg·L- 1 ;BCEF对MAO A ,B抑制呈混合型抑制作用 ,Km值分别为 1 1 97、 8 1 3μmol·L- 1 。结论　BCEF0 0 83体内外给药对大、小鼠脑组织MAO活性具有抑制作用     

Effects of d-methamphetamine on monkey brain monoamine oxidase, in vivo and in vitro

A and B form MAO activities in mitochondria and synaptosome were measured in the brain of monkeys administered d-methamphetamine (d-MP) 2 mg/kg, i.m., daily for 7 days. When mitochondria were used as an enzyme preparation, the Km and Vmax values decreased with 5-HT (serotonin for A-form MAO substrate) and beta-phenylethylamine (beta-PEA for B-form MAO substrate), while in the synaptosome, a significant increase of the Km and Vmax values was observed with 5-HT and dopamine as substrates. The mitochondrial MAO treated with d-MP was inhibited strongly by clorgyline and deprenyl with beta-PEA as a substrate, while synaptosomal MAO was highly sensitive to these MAO inhibitors with 5-HT as a substrate. MP and amphetamine (AP) were found in brain mitochondrial and synaptosomal preparations of monkeys administered 2 mg/kg d-MP, i.m. daily for 7 days; MP and AP contents were 5.05 +/- 0.22 pg/mg protein and 37.3 +/- 3.8 ng/mg protein in mitochondria and 2.35 +/- 0.35 pg/mg protein and 46.4 +/- 1.5 ng/mg protein in synaptosomes, respectively. MAO was inhibited by MP and its metabolites, AP p-hydroxymethamphetamine (OH-MP) and p-hydroxyamphetamine (OH-AP), with 5-HT, beta-PEA and dopamine as substrates, in vitro. MP and its metabolites were more potent inhibitors of A-form MAO than B-form MAO.     

Inhibition of brain mitochondrial monoamine oxidases by the endogenous compound 5-hydroxyoxindole

5-Hydroxyoxindole is a recently identified endogenous compound. Its physiological role remains unclear but certain evidence exists, that it may share some regulatory properties with isatin, a known endogenous inhibitor of monoamine oxidase (MAO) type B (MAO-B). In this study several oxidized indoles were tested for their in vitro inhibition of MAO type A (MAO-A) and B of rat brain non-synaptic mitochondria. 5-Hydroxyoxindole was less potent MAO-A inhibitor (IC50 56.8 microM) than isatin (31.8 microM) and especially 5-hydroxyisatin (6.5 microM), but it was the only highly selective MAO-A inhibitor among the all compounds studied (IC50 MAO-A:IC50 MAO-B = 0.044). Thus, the in vitro data suggest that MAO-A may represent potential target for 5-hydroxyoxindole.     

Antidepressant Effect of Baicalin Extracted from the Root of Scutellaria baicalensis. in Mice and Rats

Abstract

The flavonoid baicalin, isolated from the dried root of Scutellaria baicalensis. G. (Labiatae), is widely used in traditional Chinese herbal medicine. In the present study, baicalin, at doses of 20, 40, and 80 mg/kg (p.o.), reduced immobility time in tail suspension test (TST) and the forced swimming test (FST) in mice. Baicalin also decreased immobility time at 12.5, 25, and 50 mg/kg (p.o.) in FST in rats. Furthermore, baicalin (25 mg/kg), as well as fluoxetine (FLU; 20 mg/kg), showed a significant recovery in sucrose intake compared with the vehicle-treated stressed animals for 5 weeks treatment in a chronic mild stress (CMS) model in rats. The effect of baicalin at the dose of 25 mg was as potent as that of reference antidepressant FLU (20 mg/kg) in the CMS model. With the monoamine oxidase (MAO A and B) assay, oral administration of baicalin at the doses of 12.5, 25, and 50 mg/kg significantly inhibited MAO A activity in a dose-dependent manner in rats. However, only baicalin at the doses of 25 and 50 mg/kg markedly inhibited MAO B activity. Neither baicalin nor FLU, at the doses tested, produced a significant effect on locomotor activity in mice. These results suggest that baicalin had a specific antidepressant-like effect in vivo.. The antidepressant activity of baicalin may be mediated in part through MAO A and B inhibition in rat brain.     

串果藤中甘草素和异甘草素对大鼠单胺氧化酶的体外抑制作用(英文)

目的:研究串果藤中甘草素和异甘草素体外对单胺氧化酶A型和B型的抑制作用.方法:根据不同的离心速度制备大鼠全脑粗线粒体作为单胺氧化酶的酶源;分别以5-羟基[侧链-2-~(14)C]色胺肌酸硫酸盐([~(14)C]5-HT)和2-苯基[1-~(14)C]乙基胺盐酸盐([~(14)C]β-PEA)为单胺氧化酶A型和B型放射性底物,用液体闪烁技术,研究甘草素和异甘草素酶抑制作用和抑制类型.结果:甘草素和异甘草素对单胺氧化酶A型和B型均具有抑制作用,呈良好的量效关系,对单胺氧化酶A型的IC_(50)(95％的可信限)分别为32(26-36)μmol/L和13.9(12.8-15.6)μmol/L,对单胺氧化酶B型的IC_(50)值分别为104.6(89.0-118.9)μmol/L和47.2(39.5-54.5)μmol/L.酶抑制特征曲线显示甘草素和异甘草素对单胺氧化酶A型呈非竞争性抑制,K_i值分别为31.5μmol/L和14.3μmol/L,而对单胺氧化酶B型呈混合竞争性抑制,K_i值分别为164.7μmol/L和62.2μmol/L,K_I值分别为15.2μmol/L和9.3μmol/L.结论:甘草素和异甘草素体外对单胺氧化酶A型呈非竞争性抑制作用,对单胺氧化酶B型呈混合竞争性抑制作用.     

Rat and human cardiac monoamine oxidase: a comparison with other tissues

Experiments were made to test the proposal that rat heart mitochondrial monoamine oxidase (MAO) differs from that in certain other organs. Using kynuramine as the substrate, cardiac MAO of rats was compared with that in the vas deferens and liver. While the relative proportions of type A and B MAO varied between the three tissues, the sensitivity of the MAO types to preferential inhibitors, mixed substrate interactions and apparent Km determinations failed to reveal differences. Human atria contained mostly type B MAO, but the properties of the A and B types were not radically different from those found in rat tissues. No clorgyline-resistant MAO activity was detected with kynuramine, either in the rat or human tissues. Differences in rat heart MAO seem to be exposed by some substrates but not others, such as kynuramine.     

Tranylcypromine enhancement of nicotine self-administration

Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.     

Characteristics of monoamine oxidase in mitochondria isolated from chick brain,liver, kidney and heart

The substrate- and inhibitor-related characteristics of monoamine oxidase (MAO) were studied with mitochondria of chick brain, liver, kidney and heart. The kinetic constants for MAO in these organs were determined, using 5-hydroxytryptamine (5-HT), tyramine and β-phenylethylamine (PEA) as substrates. For all the substrates, the V_max values were highest in kidney, followed in decreasing order by brain, liver and heart. For tyramine and PEA, the K_m values were lowest in liver, but for 5-HT it was lowest in heart. Inhibition experiments with clorgyline and deprenyl were carried out on mitochondria of the four organs with the three substrates at their K_m concentrations. From the plateaus observed of inhibition by clorgyline, it was concluded that 5-HT was oxidized by both types of MAO in mitochondria of all the organs; PEA was fairly specific for type B MAO in brain, liver and kidney, but non-specific in heart. In heart mitochondria, appreciable amounts of the activities toward tyramine and PEA were due to an amine oxidase distinct from mitochondrial MAO; 5-HT, however, was oxidized exclusively by mitochondrial MAO in this organ. The above atypical characteristics in substrate specificity found in chick tissues support the idea that the type A and type B concept cannot be applied uncritically to all tissues from all species.     

Effects of monoamine oxidase inhibitors on levels of catechols and homovanillic acid in striatum and plasma

Levels of homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in plasma and the striatium were measured after inhibition of monoamine oxidase type A (MAO-A) by clorgyline (4 mg/kg i.p.), MAO-B by (-)deprenyl (1 mg/kg i.p.), both MAO-A and MAO-B by nialamide (75 mg/kg i.p.) or peripheral neuronal MAO by debrisoquin (40 mg/kg i.p.). Levels of HVA in plasma decreased by about 60% after single doses of nialamide or clorgyline, by about 80% after repeated doses of nialamide, by about 40% after a single dose of debrisoquin and by about 50% after repeated doses of debrisoquin. The administration of clorgyline, nialamide or debrisoquin significantly decreased concentrations of DOPAC and DHPG in plasma, whereas (-)deprenyl did not affect levels of DHPG or HVA. None of the MAO inhibitors produced more than about 80% depression of levels of any of the deaminated metabolites. The results suggest that most of the HVA in plasma is derived from deamination of DA by MAO-A in peripheral neurons; that DOPAC in plasma is derived from cells outside the central nervous system; that DHPG in plasma is derived virtually exclusively from the metabolism of norepinephrine in sympathetic nerve endings and that residual levels of HVA after treatment with debrisoquin provide an improved but limited indication of central dopaminergic activity.     

Monoamine oxidase inhibition cannot account for changes in visual evoked potentials produced by chlordimeform

Chlordimeform (CDM), a formamidine insecticide and monoamine oxidase (MAO) inhibitor, has recently been shown to produce large changes in visual evoked potentials of hooded rats (Boyes and Dyer, 1984a). Two experiments were performed to determine if the changes in evoked potentials were a result of the inhibition of MAO. In the first, the degree of inhibition of MAO in the brains of rats treated with chlordimeform (1.0-100 mg/kg, i.p.) was compared with that produced by pargyline (0.3-30 mg/kg, i.p.). Both compounds preferentially inhibited MAO-B, although MAO-A was substantially inhibited at larger doses. Pargyline was a relatively more potent inhibitor of MAO than chlordimeform, but not more efficacious. In the second experiment, pattern reversal evoked potentials (PREPs) and flash-evoked potentials (FEPs) were recorded from groups of rats after treatment with either saline, 0.4 mg/kg pargyline, 20 mg/kg pargyline or 40 mg/kg chlordimeform. The latter two groups were selected so as to have similar levels of inhibition of MAO, about 90% inhibition of MAO-B and 60% inhibition of MAO-A. The results showed a doubling of the amplitude of pattern reversal evoked potentials and increased latencies of the pattern reversal evoked potential and the flash-evoked-potentials in the chlordimeform-treated group, but no significant changes from saline control values in the pargyline-treated groups. These results confirm that chlordimeform is a MAO inhibitor at doses which produce behavioral and electrophysiological changes, but demonstrate further that the changes in visual evoked potentials produced by chlordimeform are not a direct result of the inhibition of MAO.