左旋多巴/ 卡比多巴联合恩他卡朋治疗帕金森病的临床研究

目的:观察左旋多巴/卡比多巴联合恩他卡朋(levodopa/carbidopa combined with entacapone,LC+E)治疗帕金森病(Parkinson's disease,PD)的临床效果。方法:选择我院2013年1月~2014年6月收治的112例PD患者,随机分为两组。其中对照组52例采用左旋多巴/卡比多巴(LC)治疗,观察组60例采用左旋多巴/卡比多巴联合恩他卡朋(LC+E)治疗。观察并比较两组治疗前后帕金森病评分量表(Unified Parkinson's Disease Rating Scale,UPDRS)的评分变化情况。结果:与治疗前比较,治疗后两组UPDRS-II日常生活能力评分,UPDRS-III运动能力评分显著下降,而UPDRS-VI SCHWABENGLAND日常活动能力评分显著上升,差异有统计学意义(P0.05);观察组各项变化情况比对照组明显,差异有统计学意义(P0.05)。两组UPDRS-I精神、行为、情绪和Hoehn与Yahr分级均无显著改善,差异无统计学意义(P0.05)。结论:左旋多巴/卡比多巴联合恩他卡朋可明显缓解PD症状,疗效优于左旋多巴/卡比多巴治疗,且安全性高,值得临床推广。     

消化道多巴胺的来源、代谢和功能

多巴胺(dopamine, DA)是一种广泛存在于中枢神经系统和外周组织的儿茶酚胺类神经递质,其功能越来越受到学者们的关注,尤其是近年发现DA可以调节免疫系统功能,DA与肠黏膜炎症相关疾病联系的研究成为热点。消化道是外周DA的重要来源,DA不仅产生于肠神经系统和消化道上皮等部位,而且还大量产自于肠道微生物。机体组织中DA的含量变化除了受其合成酶影响外,还受到两个重要的代谢酶——单胺氧化酶(monoamine oxidase, MAO)和儿茶酚-O-甲基转移酶(catechol-O-methyltransferase, COMT)的调控。本文主要对消化道DA的来源和功能、DA代谢酶的分布和功能进行综述。     

帕金森病的临床治疗概况

帕金森病(Parkinson's disease, PD),在医学上称为"原发性震颤麻痹",又称"震颤麻痹",是一种中枢神经系统变性疾病,主要是因位于中脑部位"黑质"中的多巴胺(DA)能神经元病理性改变后,多巴胺的合成减少,对与其功能相互拮抗的乙酰胆碱的抑制功能降低,则乙酰胆碱的兴奋作用相对增强。两者失衡的结果便出现了"震颤麻痹"。本综述先从PD发病机制方向总结归纳目前临床常用的西医药物(包括左旋多巴、DA降解酶抑制剂、DA受体激动剂、抗胆碱能药物)、基因治疗靶点、手术治疗(脑深部电刺激术)及物理疗法,又从中医角度整体介绍了目前中医中药治疗以及针灸治疗等。因PD对患者的日常生活及身心健康造成了严重影响,我们希望通过本综述为PD综合治疗提供更广阔的临床思路及更好的方案。     

多巴胺对昆虫生殖的调控

多巴胺(dopamine, DA)可以调节昆虫的生殖行为,促进昆虫生殖系统的成熟发育.雄性果蝇(Drosophila)性行为受脑后外侧多巴胺能神经元(PPL2ab)调节,这些神经元的DA合成能力影响雄虫之间以及雌雄之间的求偶行为.果蝇雄成虫脑内DA含量影响性取向, DA水平过高或过低都会诱发雄性果蝇之间的同性求偶行为. DA还参与昆虫生殖行为转变和交配后行为的调节. DA可以作为神经激素,调节昆虫的味觉和嗅觉感受,中枢神经系统内DA对昆虫生殖行为的调节涉及多巴胺/蜕皮激素受体(DopEcR)和蜕皮酮的协同作用,果蝇后脑P1神经元在雄虫求偶信息回路中发挥重要作用. DA可以促进卵成熟发育,调节社会性昆虫生殖状态.对卵成熟发育的促进与DA受体表达的发育阶段性差异有关,并涉及DA、章鱼胺(octopamine, OA)、保幼激素(juvenile hormone, JH)、蜕皮激素(molting hormone, MH)之间的相互作用.黑腹果蝇幼龄雌虫咽侧体(corpus allatum, CA)内多巴胺D2型受体(DD2R)表达水平远低于性成熟雌虫,多巴胺D1型受体(DopR)表达水平远高于成熟雌虫,而DD2R在性成熟雌虫咽侧体内的表达水平远高于幼龄雌虫. DopR, DD2R在脂肪体细胞中的表达情况与CA相反. DA, JH, MH, OA之间的互作通过对相关基因表达和代谢酶活性调节实现.上述激素间的互作还涉及类胰岛素(insulin-like peptides, ILPs)及其信号途径.蜜蜂工蜂的生殖状态受蜂王上颚信息素(queen’s mandibular gland pheromone, QMP)、幼虫信息素、卵巢D2型受体基因的调节. DA对昆虫生殖调控的研究,可以为新药剂开发以及人类脑科学和神经系统疾病机制研究提供参考.     

多巴胺代谢异常在帕金森病相关病理变化中的作用

帕金森病(Parkinson's disease,PD)是常见的中枢神经系统退行性疾病之一,其主要病理学特征是中脑黑质部的多巴胺(dopamine,DA)能神经元选择性丢失.虽然已发现基因易感性、衰老、环境毒素等因素与PD发病有关,但导致DA能神经元退行性死亡的细胞分子机制仍不明确.DA代谢是DA能神经元中的重要生理过...     

5-HT和DA对虾蟹打斗行为影响的研究进展

5-羟色胺(5-HT)和多巴胺(DA)是两种神经递质,可与众多不同类型的受体结合发挥多种重要的生理功能.现已证明其广泛分布于多种动物的不同组织中,在动物的打斗行为活动中起着重要的调节作用.目前,在虾蟹中已被报道的5-HT受体主要有5种,分别是5-HT1A、5-HT1B、5HT2A、5HT2B和5-HT7;DA受体主要为DA1A、DA1B、DA2和DA4.5-HT和DA及其受体分布存在明显的种属和组织特异性.5-HT和DA参于了虾蟹打斗行为的调节过程并有不同的调节机理.5-HT可以调节环磷酸腺苷(cAMP)或高血糖激素(CHH)的释放,促进或抑制虾蟹打斗行为;而DA同样能够通过调节cAMP及COMT等物质的释放来调节虾蟹打斗行为.     

胶质细胞在帕金森病神经元铁聚积及退变中的作用

越来越多的证据表明胶质细胞在中枢神经系统发育、神经元的存活、神经修复与再生、突触传递及免疫炎症等方面均具有重要的功能。近年来,胶质细胞在帕金森病(Parkinson’s disease,PD)中的作用受到越来越多的关注。大量的研究证实,中脑黑质(substantia nigra,SN)部位铁聚积参与了PD多巴胺(dopamine,DA)神经元的死亡。目前PD铁沉积的研究主要集中在DA神经元,但实际上脑内胶质细胞在中枢神经系统铁稳态调节中发挥着重要的作用。因此,本文综述了胶质细胞铁代谢及其参与DA神经元铁聚积及死亡的作用机制,为揭示PD患者SN部位铁聚积的机制以及发现潜在的治疗靶点提供理论依据。     

正电子发射断层扫描技术已应用于帕金森氏症研究

帕金森氏症(Parkinson's disease,PD)是以黑质纹状体通路受损、纹状体多巴胺(DA)含量减少为主要病理特征的一种神经系统疾病。以往对PD的病理过程研究主要是在患者死后进行的,因此患者生前的病理资料很难得到。最近,正电子发射断层扫描技术在PD病理研究中的应用,在很大程度上弥补了上述缺陷。正电子发射断层扫描(positron emission tomography,PET)是一种新的核医学影像技术,其原理是将标记正电子发射的同位素药物注入机体,通过断层扫描观察药物在生物体内某些部位的分布和代谢,以此定量测定脑的血流动力学.代谢、受体药理学和神经递质的代谢状况。它的优点是可以同时兼顾形态学与机能学的观察。     

人胚胎干细胞来源多巴胺前体细胞治疗帕金森病猴

帕金森病(Parkinson’s disease,PD)是一种常见于中老年人的神经系统退行性疾病,由中脑腹侧的多巴胺能(dopaminergic,DA)神经元缺失造成。这类疾病可通过移植由人胚胎干细胞(human embryonic stem cells,h ESC)或其他途径获得的多巴胺能神经元实现治疗。然而,在应用于临床之前,需要对这些多巴胺能神经元的安全性和有效性在合适的动物模型中进行充分、全面的评价。为评价由临床级人胚胎干细胞分化的多巴胺能神经元是否安全、有效,根据先导专项部署,我们建立了MPTP诱导的帕金森病猴模型,并将由人胚胎干细胞定向分化的多巴胺能神经元植入受损猴脑区。结果表明,在所有接受细胞移植的猴中,未发生移植细胞形成的肿瘤和继发肿瘤。移植细胞可分化为多巴胺能神经元并使局部多巴胺水平提高,带来不同程度的行为学改善。这些发现提示,多能干细胞分化的多巴胺能神经元移植治疗帕金森病安全、有效,可进一步应用于帕金森病的治疗。     

多巴胺转运体功能及其与神经精神疾病的相关研究

中枢神经系统(central nervous system,CNS)环路是注意力、奖赏应答和动机等精神活动的基础,而神经递质多巴胺(dopamine,DA)在这一环路中起关键作用。多巴胺转运体(dopamine transport,DAT)位于突触前体,重新摄取DA,维持突触多巴胺有效性和多巴胺能神经元的协调性。多巴胺转运体功能异常会导致脑内多巴胺平衡失调,从而引起精神兴奋剂依赖、帕金森病(Parkinson disease,PD)、精神分裂症及注意力缺陷多动障碍(attention-deficit hyperactivity disorder,ADHD)等多种神经精神疾病。本文从DAT的结构与功能及其在多巴胺信号调节中的分子机制,DAT与精神兴奋剂依赖等疾病关系的相关研究进行了论述。     

五羟色胺和多巴胺与攻击行为的关联研究进展

五羟色胺（5-HT）和多巴胺（DA）是影响攻击行为的重要神经递质。参与这两种神经递质合成和分解、运输及信号转导等过程的物质均可能影响攻击行为,如影响5-HT作用的色氨酸、色氨酸羟化酶、单胺氧化酶、5-羟吲哚乙酸及5-HT转运体和5-HT受体;影响DA作用的多巴胺β羟化酶和儿茶酚胺邻位甲基转移酶以及DA转运体。未来攻击行为研究,应考虑色氨酸自身代谢、受体亚型及其他单胺类和儿茶酚胺类神经递质的影响。将肠道微生物纳入攻击行为研究也是未来研究的新方向。     

Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase

Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol–O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson’s disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC₅₀ values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC₅₀ value of 0.048 μM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC₅₀ value of 0.23 μM. The results indicated that the pyrazoline derivatives (IC₅₀ = 0.048–0.21 µM) are more potent COMT inhibitors than the chalcones (IC₅₀ = 0.14–0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC₅₀ values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.     

Focus: The Aging Brain: Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology

Dopamine agonists (DA) are therapeutic agents that are commonly used in the treatment of Parkinson’s disease (PD). They can reduce undesired motor fluctuations and delay the administration of levodopa therapy. However, this drug family is associated with specific side effects that can significantly diminish the quality of life among PD patients. Some of them impose significant risks for individuals who have a history of cardiovascular diseases, psychosis, and depression, or those older patients who suffer from renal or hepatic insufficiency. Various pharmacokinetic and pharmacodynamic considerations need to be taken into account when administering DA therapy. The goal of this review is to provide a comprehensive, up-to-date overview of DA therapeutic modalities for PD.     

Catechol-O-methyltransferase inhibition protects against 3,4-dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new insights into levodopa toxicity

Inhibition of catechol-O-methyltransferase (COMT) has protective effects on levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589]. Here, we extend our recent studies to elucidate the mechanisms of these protective effects. Thus, we investigated the effects of all main L-DOPA/DA metabolites on survival of tyrosine hydroxylase immunoreactive (THir) neurons in primary rat mesencephalic cultures. 3-O-Methyldopa, homovanillic acid, dihydroxyphenyl acetate and 3-methoxytyramine had no effects at concentrations up to 300 micro M after 24h, whereas DA was more toxic than L-DOPA with toxicity at concentrations of >or=1 micro M. The coenzyme of COMT, S-adenosyl-L-methionine (SAM), and its demethylated product S-adenosylhomocystein caused no relevant alteration of THir neuron survival or L-DOPA toxicity. In contrast, inhibition of SAM synthesis by selenomethionine showed time- and dose-dependent increase of THir neuron survival, but did not affect L-DOPA toxicity. L-DOPA-induced lipid peroxidation in mesencephalic cultures was not modified by the COMT inhibitor Ro 41-0960 (1 micro M). Increased contamination of the cultures with glial cells attenuated L- and D-DOPA toxicity, but caused significant enhancement of protection by COMT inhibitors against L-DOPA toxicity only. Investigations of L-DOPA uptake in rat striatal cultures using HPLC revealed a significant reduction of extracellular L-DOPA concentrations by Ro 41-0960. Our data confirm that L-DOPA toxicity towards DA neurons is mediated by an autooxidative process, which is attenuated by glial cells. In addition, we demonstrate a second mechanism of L-DOPA toxicity in vitro mediated by a COMT- and glia-dependent pathway, which is blocked by COMT inhibitors, most likely due to enhanced glial uptake of L-DOPA.     

Polymorphism of the COMT,MAO, DAT,NET and 5-HTT Genes,and Biogenic Amines in Parkinson’s Disease

Epinephrine (E) and sympathetic nerve stimulation were described by Thomas Renton Elliott in 1905 for the first time. Dopamine (DA), norepinephrine (NE), E, and serotonin (5-HT) belong to the classic biogenic amines (or monoamines). Parkinson’s disease (PD) is among the diseases in which it has been established that catecholamines may account for the neurodegeneration of central and peripheral catecholamine neural systems. PD is a chronic and progressive neurological disorder characterized by resting tremor, rigidity, and bradykinesia, affecting 2% of individuals above the age of 65 years. This disorder is a result of degeneration of DA-producing neurons of the substantia nigra and a significant loss of noradrenergic neurons in the locus coeruleus. In PD and other related neurodegerative diseases, catecholamines play the role of endogenous neurotoxins. Catechol-O-methyltransferase (COMT) and/or monoamine oxidase (MAO) catalyze the metabolism of monoamines. However, the monoamine transporters for DA, NE, and 5-HT namely DAT, NET, and SERT, respectively regulate the monoamine concentration. The metabolism of catecholamines and 5-HT involves common factors. Monoamine transporters represent targets for many pharmacological agents that affect brain function, including psychostimulators and antidepressants. In PD, polymorphisms of the COMT, MAO, DAT, NET, and 5- HTT genes may change the levels of biogenic amines and their metabolic products. The currently available therapies for PD improve the symptoms but do not halt the progression of the disease. The most effective treatment for PD patients is therapy with L-dopa. Combined therapy for PD involves a DA agonist and decarboxylase, MAOs and COMT inhibitors, and is the current optimal form of PD treatment maintaining monoamine balance.     

Entacapone Reduces Cortical Activation in Parkinson's Disease with Wearing-Off: A f-MRI Study

Background and Purpose

Wearing-off is one of the most frequent problems encountered by levodopa-treated patients. Entacapone, a peripheral inhibitor of catechol-O-methyltransferase (COMT), reduces this motor complication by prolonging the effect of levodopa. We sought to understand the impact of COMT-inhibition on movement execution in PD patients with wearing-off by comparing functional magnetic resonance imaging (f-MRI) activation patterns prior to and during entacapone treatment. Our hypothesis was to determine whether changes in cortical activation are associated to COMT-inhibitor treatment.

Methods

Nine levodopa-treated non-demented PD patients with wearing-off were prospectively studied in two f-MRI session, prior to and during entacapone treatment. A group of control subjects were also studied for comparison.

Results

The patients significantly improved under COMT-inhibitor treatment based on home diaries. F-MRI results showed that at baseline the patients presented a bilateral activation of the primary motor, controlateral premotor cortex and supplementary motor area, as well as ipsilateral cerebellum. During treatment with entacapone, PD patients showed reductions in the activations of these cortical areas and a decreased activation in the ipsilateral cerebellum.

Conclusions

Our preliminary findings indicate that f-MRI is able to detect cortical activation changes during long-term modulation of dopaminergic treatment in PD patients with wearing-off, and thus, this technique could be further investigated in advanced PD patients.     

β3肾上腺素受体介导多巴胺对大鼠远端结肠运动的抑制作用

目的研究多巴胺（DA）对大鼠结肠运动影响的机制。方法采用离体组织灌流方法记录大鼠远端结肠自发性节律运动,观察DA的作用以及阻断剂的影响,再用反转录实时多聚酶链反应（real time RT-PCR）检测受体基因的表达。结果DA（≥1.0×10-5mol/L）对结肠远端（紧接肛门淋巴结近端）离体纵行肌条（2.0 mm×10 mm）的运动具有抑制作用,多巴胺受体阻断剂（D1受体阻断剂SCH23390,1.0×10-7mol/L,D2受体阻断剂Sulpide,1.0×10-7mol/L）不能阻断多巴胺的抑制效应,但加入β3受体抑制剂cyanopindolol（7.5×10-7mol/L）,DA的抑制作用显著减弱。real time RT-PCR检测发现β1、β2、β3受体mRNA在远端结肠均有表达。结论DA可通过β3受体发挥对远端结肠运动的抑制作用。     

Effects of Catechol-O-Methyltransferase Inhibitors and L-3,4-Dihydroxyphenylalanine With or Without Carbidopa on Extracellular Dopamine in Rat Striatum

Abstract: The effects of two new catechol- O -methyltransferase (COMT) inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3- O -methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT inhibitors markedly inhibit the O -methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation. A significant effect can be achieved even by inhibiting only the peripheral COMT activity. The data suggest that COMT inhibitors may be of clinical importance as adjuncts in the treatment of Parkinson's disease.     

Age-related motor and catecholomine alterations in mice on levodopa supplemented diet

Old mice reared on regular diet show reduced motor activity, decreased basal adenylate cyclase, and increased MAO activities compared to adults. Brain DDC and COMT activities, DA, NE levels and DA-stimulated adenylate cyclase remained unchanged. By contrast, mice fed levodopa for life did not develop decreased motor activity with aging, lived about 50% longer, had slightly elevated whole brain DA and NE levels and failed to develop the expected rise in MAO activity with aging. Levodopa did not alter the number of dopaminergic and muscarinic cholinergic receptors or the adenylate cyclase activity in the striatum during aging. On levodopa, hepatic and renal DA, dopa, and HVA increased but the latter two returned to basal levels by mid life. In liver, DDC was unchanged but MAO tended to be higher in levodopa-fed mice. Thus, motor impairment is an age-related phenomenon in mice associated with selective alterations in brain dopaminergic systems, which may be prevented by dietary levodopa. Extracerebral tissues, through possibly adaptive metabolic mechanisms, play a significant role in regulating brain catecholamines during chronic administration of large doses of levodopa.     

Increased catechol-O-methyltransferase activity and protein expression in OX-42-positive cells in the substantia nigra after lipopolysaccharide microinfusion

Activated microglial cells are found in the substantia nigra and the striatum of Parkinson's disease patients. These cells have been shown to express catechol-O-methyltransferase activity which may increase during pathological conditions. Lipopolysaccharides are potent activators of microglial cells. After paranigral lipopolysaccharide infusion to rats we observed intense microglial activation around the lesion area followed by a delayed injury in nigrostriatal pathway in 2 weeks. Simultaneously, catechol-O-methyltransferase activity in the substantia nigra was gradually increased up to 213%. In the Western blot the amount of soluble COMT and membrane bound COMT proteins were increased by 255% and 86%, respectively. Increased catechol-O-methyltransferase immunoreactivity was located primarily into the activated microglial cells in the lesion area. Interestingly, catechol-O-methyltransferase and OX-42 stained also intensively microglia/macrophage-like cells which surrounded the adjacent blood vessels. Inhibition of catechol-O-methyltransferase activity by tolcapone or entacapone did not increase lipopolysaccharide-induced neurotoxicity. We conclude that catechol-O-methyltransferase activity and protein expression were increased in the substantia nigra after inflammation induced by lipopolysaccharides. These changes in glial and perivascular catechol-O-methyltransferase activity may have clinical relevance for Parkinson's disease drug treatment due to increased metabolism of levodopa in the brain.