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     

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。     

新癀片及其中药组分对次黄嘌呤致高尿酸小鼠的影响

目的探讨新癀片及其中药组分对次黄嘌呤所致的高尿酸小鼠的影响,并初步探讨其机制。方法采用腹腔注射次黄嘌呤引起的高尿酸小鼠动物模型和正常小鼠,分别以新癀片及其中药组分不同剂量组进行灌胃,给药结束后测定血尿酸水平以及肝脏中黄嘌呤氧化酶活性。结果腹腔注射次黄嘌呤1h后,阳性组、新癀片低中高剂量组(23.75、47.5、95mg·kg-1)、新癀片中药组分低中高剂量组(23.75、47.5、95mg·kg-1),能明显对抗次黄嘌呤引起的高尿酸作用(P<0.01),且对肝脏中黄嘌呤氧化酶的活性有一定程度的抑制作用。结论新癀片及其中药组分可能通过抑制黄嘌呤氧化酶的活性来降低血尿酸水平。     

脑得安胶囊的药理作用研究

本文初步研究了脑得安的药理作用．最大耐受量试验表明其LD50大于54g／kg；对醋酸致小白鼠扭体反应的影响结果表明，脑得安胶囊1．0g／kg和2．0g／kg（po）可显著减少小鼠的扭体次数；脑得安对二甲苯致小鼠耳廓炎症亦有显著抑制作用，脑得安2．0g／kg组的抑制作用与阿斯匹林（0．6g／kg，po）的作用效果相当．热板镇痛实验的结果显示，脑得安1．0g／kg和2．0g／kg（po）给药后30min，60min，120min均可显著提高小鼠的痛反应阈值．本实验结果表明脑得安具有明显的镇痛消炎作用．     

蚕沙水提物对次黄嘌呤致急性高尿酸血症小鼠血尿酸含量的影响

目的研究蚕沙水提物对次黄嘌呤致高尿酸血症小鼠血尿酸含量的影响。方法给正常组和模型组小鼠灌胃蒸馏水20mL/kg;给高、中、低剂量组小鼠灌胃蚕沙水提物,剂量分别为3.6、1.8、1.0g生药/kg,每日1次,连续7d。末次灌胃后1h,除正常组外其余各组腹腔注射次黄嘌呤100mg/kg,造成模型组急性高尿酸血症,半小时后取血测定血尿酸含量。结果小鼠注射次黄嘌呤后半小时,模型组小鼠血尿酸含量明显高于正常组,P<0.05,组间差异有显著性意义。高、中、低剂量组连续给药7d后腹腔注射次黄嘌呤,只有高剂量组小鼠血尿酸含量低于模型组,P<0.05,组间差异有显著性意义。结论模型组小鼠腹腔注射次黄嘌呤1mg/kg可致高尿酸血症。高剂量(3.6g生药/kg)蚕沙水提物预防性给药能抑制次黄嘌呤致小鼠急性高尿酸血症。     

喜树碱钠对小鼠肿瘤相伴免疫性影响的研究

喜树碱是我国应用的一种抗癌新药。本文进一步研究了药物对小鼠免疫活性的影响,结果如下: 本实验采用肝癌和网织细胞肉瘤二株小鼠移植瘤,实验证明带瘤小鼠能排斥第二次同种肿瘤移植,这种现象称为肿瘤相伴免疫(CTI)。我们以CTI为指标观察了喜树碱的免疫抑制作用。给小鼠腹腔注射喜树碱1mg/kg连续9天时,对免疫有明显的抑制作用;每4天给药一次,有中等抑制;而40mg/kg一次注射的影响最小。以喜树碱12.5mg/kg注射2次,对免疫无明显影响。喜树碱对免疫的抑制作用并不持久,停药9天后免疫功能可恢复。     

枣仁安神颗粒改善睡眠作用的量效、时效关系及对脑内细胞因子的影响

目的 研究枣仁安神颗粒改善睡眠作用的量效、时效关系,及对小鼠脑内相关细胞因子的影响。方法 采用戊巴比妥钠协同睡眠试验方法,以睡眠时间为指标,研究枣仁安神颗粒改善睡眠作用的量效、时效关系;采用酶联免疫吸附测定法(ELISA)测定小鼠全脑白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)的含量。结果 枣仁安神颗粒改善睡眠作用最短起效时间为连续给药5 d;最佳给药剂量为2 080 mg/kg,在剂量为4 160 mg/kg时药效减弱,表现为复杂的量效关系;给予枣仁安神颗粒2 080 mg/kg后,小鼠全脑IL-1β和TNF-α的含量明显降低。结论 枣仁安神颗粒改善睡眠作用时效关系明显、量效关系复杂,其改善睡眠作用由细胞因子介导。     

脑栓通胶囊对痴呆小鼠脑组织MAO及海马神经元的影响

目的研究脑栓通胶囊对D-半乳糖所致痴呆小鼠脑组织MAO及海马神经元的影响。方法将36只小鼠随机均分为正常对照组、模型组、脑栓通胶囊组和脑复康阳性对照组。模型组、脑栓通胶囊组和脑复康阳性对照组每天皮下注射D-半乳糖120mg/kg,连续注射6周;正常对照组每天皮下注射同等体积的生理盐水;模型对照组与正常对照组每天灌胃等量的生理盐水,脑栓通胶囊组灌胃量1.35粒/(kg.d),脑复康组灌胃量0.36g/(kg.d)。实验结束后,测定脑组织MAO活性及光镜下观察小鼠大脑海马形态学改变。结果模型组小鼠脑组织MAO活性升高,海马区出现病理形态学改变,经脑栓通胶囊治疗后小鼠脑组织MAO活性降低,形态学病理改变减轻,与正常对照组比较差异无统计学意义。结论初步表明脑栓通胶囊能降低MAO活性,保护海马神经元,可用于预防和治疗MAO活性增高导致的相关疾病。     

螺旋藻多糖对D-半乳糖所致衰老小鼠的作用

雌性NIH小鼠每天颈背scD-半乳糖80mg／kg，连续42d，造成亚急性衰老模型。同时每天分别ig螺旋藻多糖（PSP）200、100mg／kg，能显著拮抗D-半乳精的作用，使小鼠肝、脑MAO－B活性显著降低，心、脑Na－K－ATP酶活性回升；能明显促进ConA诱导的小鼠淋巴细胞增殖转化，并使小鼠皮肤羟脯氨酸含量明显增加。提示PSP对D-半乳糖所致衰老小鼠有明显的改善作用。     

复方前列宝抑制前列腺增生及抗炎作用的研究

复方前列宝口服或腹腔注射给药均能明显抑制由丙酸睾丸酮(50mg/kg)引起的小鼠前列腺增生。其口服剂量200mg/kg、腹腔注射剂量400mg/kg时与阳性药物安尿通的口服剂量800mg/kg、腹腔注射剂量1200mg/kg的药效相近。小鼠口服复方前列宝后,对角叉莱胶引起的足趾肿胀有明显的抑制作用,其剂量为400mg/kg时的抑制作用较氢化可的松25mg/kg时强。     

Interaction of psychotropic drugs with monoamine oxidase in rat brain

Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.     

Effect of diethylnitrosamine on monoamine oxidase in rat liver

The effect of diethylnitrosamine (DEN), a well-known experimental carcinogen, toward MAO-A and MAO-B activity of rat liver was investigated. The oxidations of both beta-PEA (MAO-B) and 5-HT (MAO-A) were inhibited by DEN. The K1 values of DEN in the inhibition of rat liver MAO-A and MAO-B activity were determined. The kinetic data show that DEN is a competitive, MAO-B selective inhibitor and its inhibitory effect on MAO-B is about 4-fold more potent than that on MAO-A. DEN might change the proportions of the multiple forms of MAO activity in tumor cells.     

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.     

Enzymic and molecular characteristics of a new form of monoamine oxidase, distinct from form-A and form-B

The present study was undertaken to clarify the enzymic and molecular properties of monoamine oxidase (MAO) in carp brain. In particular, its sensitivities to selective MAO inhibitors, kinetic properties and molecular weight were compared with those of the enzyme in carp liver. The selective and potent MAO-A and MAO-B inhibitors FLA 788(+), FLA 336(+), MD 780236 and benzylcyanide caused dose-dependent inhibitions of MAO activity in both carp brain and liver; the inhibition curves were all single-sigmoidal, and the degrees of inhibition of the activities towards 5-hydroxytryptamine (5-HT, selective MAO-A substrate), tyramine (substrate for both forms of MAO) and beta-phenylethylamine (PEA, selective MAO-B substrate) were similar. This was also the case for inhibition of activity in carp brain by the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and I-deprenyl, indicating the presence in both preparations of a single MAO which differs from either form of MAO. Studies on the substrate specificities and Km values for these three substrates and the inhibitory effects of some compounds suggested that the enzymic characters of MAO in carp preparations were similar and that these enzymes might be FAD-containing enzymes, like MAO in various mammals. By labelling the preparations with radioactive pargyline and then subjecting them to sodium dodecyl sulfate electrophoresis, the apparent molecular weights of carp brain and liver MAO were estimated as 60,000 daltons. The same value was also obtained for rat brain and liver mitochondrial MAO-B. These results indicate that by the present definitions of MAO-A and MAO-B, MAO in carp brain and liver is similar to, but distinct from, both these forms of MAO.     

The Anticonvulsant FCE 26743 is a Selective and Short-acting MAO-B Inhibitor Devoid of Inducing Properties towards Cytochrome P450-dependent Testosterone Hydroxylation in Mice and Rats

Abstract— The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-(3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10^?7 m for MAO-B and higher than 10^?5 m for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1·1 mg kg^?1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg^?1. Similar effects were seen in liver. Following oral administration of 5 mg kg^?1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0–8 h urines after administration of a 119 mg kg^?1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.     

Inhibition by Zn(2+) of A-form monoamine oxidase in monkey brain mitochondria

The effects of ZnSO(4) on mitochondrial monoamine oxidase (MAO) activity in monkey brain were compared with those in rat and rabbit, in vitro. After preincubation at 25 degrees C for 20 min with 1 microM ZnSO(4), MAO-A activity in monkey brain was about 50% using serotonin (5-HT) as a substrate, and the inhibition was proportional to the concentration of ZnSO(4). However, ZnSO(4) had no effect on MAO-B activity in monkey brain using beta-phenylethylamine (beta-PEA) as a substrate. The inhibition by ZnSO(4) of MAO-A activity was competitive and reversible. CdSO(4) also inhibits MAO-A, but not MAO-B in monkey brain mitochondria. ZnSO(4) did not inhibit either MAO-A or MAO-B activity in rat and rabbit brain mitochondria. These results indicate that the inhibiting action of Zn(2+) differs depending on animal species. In monkey brain mitochondria, MAO-A was highly sensitive to Zn(2+) and MAO-B was less sensitive. These results also suggest that Zn(2+) may regulate the level of catecholamine content in monkey brain.     

Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: implications for the treatment of affective disorders

Psoralen and isopsoralen, furocoumarins isolated from the plant Psoralea corylifolia L., were demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. This inhibition of enzyme activities was found to be dose-dependent and reversible. For MAO-A, the IC50 values are 15.2 +/- 1.3 microM psoralen and 9.0 +/- 0.6 microM isopsoralen. For MAO-B, the IC50 values are 61.8 +/- 4.3 microM psoralen and 12.8 +/- 0.5 microM isopsoralen. Lineweaver-Burk transformation of the inhibition data indicates that inhibition by both psoralen and isopsoralen is non-competitive for MAO-A. The Ki values were calculated to be 14.0 microM for psoralen and 6.5 microM for isopsoralen. On the other hand, inhibition by both psoralen and isopsoralen is competitive for MAO-B. The Ki values were calculated to be 58.1 microM for psoralen and 10.8 microM for isopsoralen. These inhibitory actions of psoralen and isopsoralen on rat brain mitochondrial MAO activities are discussed in relation to their toxicities and their potential applications to treat affective disorders.     

Inhibition of rat brain monoamine oxidase activity by cerebral anti-ischemic agent, ifenprodil

Ifenprodil, which is clinically used as a cerebral vasodilator, inhibited rat brain type A (MAO-A) and type B (MAO-B) monoamine oxidase activity. It did not, however, affect rat lung semicarbazide-sensitive amine oxidase. The degree of inhibition of either form of MAO was not changed by 30 min preincubation of the enzyme preparations at 37 degrees C with ifenprodil. Modes of inhibition of MAO-A and MAO-B by ifenprodil were competitive towards oxidation of their respective substrates, 5-hydroxytryptamine and benzylamine, with Ki values of 75 microM for inhibition of MAO-A and 110 microM for inhibition of MAO-B.     

Drug-induced changes in motor activity after selective MAO inhibition

The increase in motor activity produced in mice by phenylethylamine (PEA), L-DOPA and amphetamine was evaluated after selective inhibition of MAO Type A (by clorgyline) or Type B (by low doses of pargyline). PEA-induced motor stimulation was intensified in the presence of MAO-B inhibition, but not when MAO-A was inhibited. This was paralleled by higher concentrations of brain and plasma PEA (after injection) in mice in which there was inhibition of MAO-B compared with control or MAO-A inhibition. Conversely, L-DOPA produced significant stimulation only when MAO-A was inhibited. The clorgyline pretreatment resulted in larger increases in brain dopamine concentrations (in the striatum, olfactory tubercles and in the area containing the substantia nigra) than did MAO-B inhibition. This effect occurred both in mice receiving L-DOPA + inhibitor and in mice receiving the inhibitor alone. Amphetamine-induced stimulation was increased following the inhibition of either form of MAO, and this was not the result of changes in the distribution or metabolism of amphetamine. These results support the concept that MAO-A and MAO-B deaminate different substrates in the rodent CNS and that amphetamine may utilize either dopamine or PEA in producing its stimulant effects.