磷酸二酯酶2对抑郁焦虑及认知障碍等中枢神经疾病的调节作用

磷酸二酯酶（Phosphodiesterase,PDE）水解细胞内第二信使-环磷酸腺苷和环磷酸鸟苷,降低细胞内第二信使的含量,进而影响下游信号转导,调节细胞内的生命活动。磷酸二酯酶2（PDE2）是磷酸二酯酶大家族的成员之一,在中枢神经系统中分布广泛,尤其在海马和杏仁核部分密集,近年来越来越多的研究表明PDE2可能参与中枢神经系统疾病的调节,而相应的PDE2抑制剂可能具有治疗抑郁、焦虑和学习记忆障碍等中枢神经系统疾病前景。本文综述了PDE2在中枢神经系统疾病调节中的作用及其抑制剂在治疗相关疾病的应用。     

磷酸二酯酶5抑制剂的研究进展

磷酸二酯酶5（PDE5）是磷酸二酯酶家族中的一员,以水解和环磷酸鸟苷为主,广泛分布于血管平滑肌和气管平滑肌,在血小板、肾脏以及阴茎海绵体也有分布。临床试验证明,PDE5抑制剂具有降低肺动脉高压、抗血栓、治疗心绞痛和勃起功能障碍等作用。综述PDE5的分子结构、调节机制以及PDE5抑制剂的构效关系和临床应用。     

米力农的临床应用及进展

米力农是一种磷酸二脂酶Ⅲ（PDEⅢ）抑制剂，作为一种非儿茶酚胺、非洋地黄类的正性肌力药，在治疗充血性心力衰竭（CHF）和扩血管等方面发挥了越来越重要的作用。在美国等多国，静脉注射米力农已被广泛用于改善心力衰竭病人的心脏功能犤１，２犦。在我国，米力农应用的时间还不长，关于此药的具体研究也尚未深入。因此本文对其药效学、药代学、临床应用及进展等情况做一综述。１．药理作用磷酸二脂酶（PDE）是一组广泛存在于心血管系统，具有反应特异性和作用底物特异性的酶。PDE通过催化环核苷酸（例如环磷酸腺苷，cAMP）的水解而终…     

环核苷酸磷酸二酯酶及其抑制剂的研究

1958年，Sutherland和Rail博士发现了cAMP及其充当第二信使调控细胞内肝糖元分解的作用。1962年，他们又发现了环核苷酸磷酸二酯酶（PDE）及其抑制剂咖啡因和它的甲基黄源呤衍生物。PDE能特异性地以3’，5’-环核苷酸为底物，催化细胞内的第二信使cAMP和cGMP，水解生成相应的无活性的5’-核苷酸。细胞内环核苷酸水平受PDE和腺（鸟）苷酸环化酶的调控，从而影响生物体的各种代谢功能。本文着重讨论PDE同功酶的分类、在体内的分布、特异性的选择性抑制剂在临床上的应用，以及研究现状。1PDE同功酶的发现和分类本世纪60年代初，PDE…     

磷酸二酯酶抑制剂治疗中枢神经系统疾病的研究进展

近年我国中枢神经系统(central nervous system diseases,CNS)疾病发病率呈升高趋势,磷酸二酯酶(phosphodiesterase,PDE)通过调节神经细胞内环磷酸腺苷和环磷酸鸟苷水平参与其发生、发展.本文简要综述了 PDE抑制剂保护CNS的作用机制以及其对临床常见CNS疾病的治疗作用,...     

磷酸二酯酶4抑制剂临床及安全性研究进展

磷酸二酯酶4 (phosphodiesterase 4, PDE4)是磷酸二酯酶家族中重要成员之一,可特异性水解环磷酸腺苷(cyclic adenosine monophosphate, cAMP),通过改变cAMP浓度引发下游磷酸化级联反应,与多种疾病密切相关。靶向PDE4的抑制剂临床研究包括呼吸系统疾病、自身免疫性疾病、中枢神经系统疾病及皮肤病等多种疾病领域。但是在已上市的PDE4抑制剂临床研究中发现,大多数药物的恶心、呕吐等胃肠道不良反应发生率较高,限制了其临床应用。因此本综述总结了已上市PDE4抑制剂的临床进展及安全性问题,结合PDE4蛋白结构分析、PDE4抑制剂的作用机制及相关不良反应机制研究,阐述了PDE4抑制剂产生不良反应的主要原因,旨在为开发安全有效的PDE4抑制剂提供参考。     

西地那非研究进展

西地那非（商品名万艾可），是一种特异性环磷酸鸟苷（cGMP)磷酸二酯酶5型（PDE5）抑制剂，通过抑制第二信使cGMP的代谢，促进海绵体动脉平滑肌舒张，进而改善勃起功能障碍（ED）症状的口服药物。本文对国外1999－2001年有关本品对心，肺，肾，眼和神经系统等方面的影响的研究进展作一介绍。     

新型磷酸二酯酶特异性抑制剂的发现及识别机制

磷酸二酯酶(PDE)通过催化水解细胞内第二信使(环磷酸腺苷cAMP,或环磷酸鸟苷cGMP),以降低细胞内cAMP或cGMP的浓度,从而中止这两个第二信使所传导的生理作用。PDEs作为新型的药物作用靶点,参与多种疾病的治疗,已成为新药研发的重要靶点。截至目前,已有多个PDE抑制剂药物上市(PDE5:5个,治疗性功能障碍和肺动脉高压;PDE4:3个,治疗慢性阻塞性肺病等),其中最出名的案例是用于治疗男性勃起功能障碍和肺动脉高压的PDE5抑制剂西地那非。然而,低选择性是这些PDE抑制剂的主要缺陷。近期我们针对PDE4,5,8,9和10等亚型,通过基于结构的药物分子设计,合成并发现多类高选择性的抑制剂。如,1)合成近150个PDE9抑制剂,从中发现抑制效应最强的高选择性先导结构3r。3r(IC_(50)=0.6 nmol·L~(-1),对PDE1选择性为788倍),活性和选择性均明显优于临床Ⅱ期的辉瑞抑制剂PF-04447943。通过晶体结构分析,发现3r与PDE9特有残基Y424形成氢键,是其具有高倍选择性的结构基础,这为PDE9高选择性抑制剂提供了新的设计策略。此外共晶结构还揭示3r和A452形成一个氢键,而PF-04447943未显示这种结合模式。通过设计与A452形成氢键,可提高化合物的抑制效应。2)合成近100个多个PDE5抑制剂,从中发现抑制剂从中发现抑制效应最强的高选择性先导结构1610。1610(IC_(50)=5.0 nmol·L~(-1),对PDE6选择性为100倍)的抑制活性与辉瑞药物西地那非相当,但选择性均明显优于西地那非(对PDE6选择性为2~3倍),动物实验也显示该类药物的抗动脉高压效果明显优于对照药物西地那非。通过分子模拟分析,发现1610进入靶标结构的Q2口袋,是1610具有100倍选择性的结构基础,这为PDE5高选择性抑制剂提供了新的设计策略。     

磷酸二酯酶抑制剂药理学作用机制和临床应用研究进展

磷酸二酯酶(phosphodiesteras,PDE)可降解机体细胞内环磷酸腺苷(cyclic adenosine monophosphate,cAMP)和环磷酸鸟苷(cyclic guanosine monophosphate,cGMP).PDE抑制剂可降低PDE活性,从而减弱其对cAMP和cGMP的降解能力.机体不...     

非选择性磷酸二酯酶抑制剂用于人工精子激活的研究进展

人工精子激活基础研究和临床辅助生殖技术治疗中应用最广泛的精子激活因子为非选择性磷酸二酯酶(PDE)抑制剂。利用非选择性PDE抑制剂处理精子能够全面抑制PDE的活性,通过加强胞内环磷酸腺苷(cAMP)信号来提升精子运动能力。基于人工精子激活的重要作用靶点PDE,综述了3种常用非选择性PDE抑制剂咖啡因、己酮可可碱和茶碱对人精子运动的激活效应的研究进展,为非选择性PDE抑制剂用于人工精子激活提供参考。     

The effects of olprinone, a phosphodiesterase 3 inhibitor, on systemic and cerebral circulation

Olprinone, a phosphodiesterase (PDE) 3 inhibitor, is used to treat heart failure due to its positive inotropic and vasodilative effects. Selective inhibition of the PDE 3 isozyme increases intracellular adenosine 3;5;-cyclic monophosphate and enhances Ca(2+) influx into cardiac muscle cells. The most significant advantage of PDE 3 inhibitors is their ability not only to enhance myocardial contraction, but to reduce, through vasodilatory action, the stress to which the heart is subjected. In peripheral vessels, the decrease of cytosolic free Ca(2+) induces the vasorelaxation of vascular smooth muscle cells. In this way, olprinone reduces mean aortic and pulmonary artery pressures. Additionally, olprinone exerts differential vasodilatory effects on peripheral vessels in each organ, based on the differences in the distribution of PDE 3 among the organs. With respect to the cerebral circulation, olprinone augments blood flow in the cerebral cortex through direct vasodilatory effects on small cerebral arteries or arterioles. Olprinone increases hepatosplanchnic blood flow and improves oxygen supply. While long-term therapy with PDE 3 inhibitors in patients with chronic heart failure may accelerate the progress of the underlying disease and provoke serious ventricular arrhythmia, olprinone shows good potential for short-term treatment in patients who have experienced severe heart failure or patients who have undergone cardiac surgery.     

Pharmacotherapy of erectile dysfunction: focus on cardiovascular safety

Therapy of erectile dysfunction has been revolutionised in recent years, as specific pharmacological inhibitors of phosphodiesterase 5 (PDE5), such as sildenafil, tadalafil, or vardenafil, were shown to be highly effective in the treatment of erectile dysfunction. They dilate arterial smooth muscle cells of the corpora cavernosa, which express PDE5 abundantly, by inhibiting the breakdown of 3’5’-cyclic guanosine monophosphate. Despite theoretical concerns of a reduced myocardial tolerance to ischaemia or promoting cardiac arrhythmias, randomised trials and retrospective analyses do not support an increased cardiac risk with oral treatment. Therapeutic doses of PDE 5 inhibitors exhibit slight blood pressure lowering effects, and do not appear to compromise coronary blood flow in coronary artery disease. However, the combination of PDE5 inhibitors with any nitric oxide donor is absolutely contraindicated because of potentially life-threatening hypotension. Before prescribing medication for erectile dysfunction, any patient with cardiovascular disease should be evaluated for a potential risk of a cardiovascular event during sexual activity according to the Princeton Consensus Panel. When a stable cardiac condition can be achieved (low risk group), oral treatment for erectile dysfunction may be appropriate.     

甘草及其黄酮类化合物的神经保护作用

甘草及其黄酮类化合物对神经元有保护作用,能对抗缺血再灌注引起的脑损伤,也有改善学习记忆和抗抑郁作用。综述甘草粗提物及其异甘草素、甘草素、甘草查耳酮、光甘草定等黄酮类化合物的神经保护作用的研究进展文献,认为甘草及其黄酮类化合物的神经保护作用是其抗炎、抗氧化、抗细胞凋亡及抗胆碱酯酶、单胺氧化酶、环磷酸腺苷磷酸二酯酶等基本药理作用综合的结果。     

Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues

Cyclic nucleotide-specific phosphodiesterases (PDEs) play a critical role in signal transduction by regulating the level of adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) in cells. The gene expression pattern of a PDE provides important information regarding its role in physiological and pathological processes. In this study, we have established the mRNA expression profile all PDE isoenzymes (PDE1A/B/C, 2A, 3A/B, 4A/B/C/D, 5A, 6A/B/C, 7A/B, 8A/B, 9A, 10A, 11A) in a human cDNA collection consisting of 10 brain regions (parietal, frontal, temporal cortex, hippocampus, striatum, thalamus, hypothalamus, substantia nigra, nucleus accumbens, cerebellum), spinal cord, dorsal root ganglia and 12 peripheral tissues (skeletal muscle, heart, thyroid, adrenal gland, pancreas, bladder, kidney, liver, lung, small intestine, spleen, and stomach). Using quantitative real-time polymerase chain reaction and parallel analysis of a carefully selected group of reference genes, we have determined the relative expression of each PDE isoenzyme across the 24 selected tissues, and also compared the expression of selected PDEs to each other within a given tissue type. Several PDEs show strikingly selective expression (e.g. PDE10A and PDE1B mRNA levels in the caudate nucleus are 20-fold higher than in most other tissues; PDE1C and PDE3A are highly expressed in the heart and PDE8B is expressed very strongly in the thyroid gland). This comprehensive approach provides a coherent and quantitative view of the mRNA expression of the PDE gene family and enables an integration of data obtained with other non-quantitative methods.     

Inhibitors of PDE1 and PDE5 cGMP phosphodiesterases: patents and therapeutic potential

Cyclic 3′5′-guanosine monophosphate (cGMP) is a key second messenger involved in the processes of intracellular signalling. Steady state levels of cGMP are modulated through a balance between the rates of formation and degradation of the nucleotide. A potential therapeutic approach to manipulation of cGMP is the inhibition of the phosphodiesterases PDE1 and PDE5. PDE5 inhibitors have been targeted by many companies and have resulted in a large number of patents. The disclosed inhibitors cover an eclectic range of polycyclic nitrogen heterocycles. Activities reported show IC50 values in the low nanomolar to subnanomolar range. A wide range of tissue, cellular and in vivo effects are also reported for these PDE5 inhibitors. By contrast, only a very few patents have appeared which claim PDE1 inhibitory activity. The potential use of PDE1 and PDE5 inhibitors in the treatment of coronary artery disease, hypertension, congestive heart failure, erectile dysfunction and pulmonary hypertension is discussed.     

Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment

Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets.     

Acute hypoxia modifies cAMP levels induced by inhibitors of phosphodiesterase-4 in rat carotid bodies,carotid arteries and superior cervical ganglia

Background and purpose:

Phosphodiesterase (PDE) inhibitors are useful to treat hypoxia-related diseases and are used in experiments studying the effects of oxygen on 3′-5′-cyclic adenosine monophosphate (cAMP) production. We studied the effects of acute hypoxia on cAMP accumulation induced by PDE inhibitors in oxygen-specific chemosensors, the carotid bodies (CBs) and in non-chemosensitive CB-related structures: carotid arteries (CAs) and superior cervical ganglia (SCG).

Experimental approach:

Concentration–response curves for the effects of a non-specific PDE inhibitor [isobutylmethylxanthine (IBMX) ], PDE4 selective inhibitors (rolipram, Ro 20-1724) and a PDE2 selective inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine) on cAMP levels were obtained in normoxic (20% O₂/5% CO₂) or hypoxic (5% O₂/5% CO₂) conditions.

Key results:

Responses to the PDE inhibitors were compatible with the presence of PDE4 in rat CBs, CAs and SCG but in the absence of PDE2 in CAs and CBs. Acute hypoxia enhanced the effects of IBMX and PDE4 inhibitors on cAMP accumulation in CAs and CBs. In SCG, acute hypoxia reduced cAMP accumulation induced by all the four PDE inhibitors tested. Differences between the effects of Ro 20-1724 and rolipram on cAMP were found in CAs and CBs during hypoxia.

Conclusions and implications:

The effects of PDE4 inhibitors could be potentiated or inhibited by acute hypoxia depending on the PDE isoforms of the tissue. The similarities between the characterization of PDE4 inhibitors at the CBs and CAs, under normoxia and hypoxia, did not support a specific role for cAMP in the oxygen-sensing machinery at the CB and suggested that no direct CB-mediated, hyperventilatory, adverse effects would be expected with administration of PDE4 inhibitors.     

复方蒲黄颗粒对局灶性脑缺血再灌注大鼠神经元凋亡及Caspase-3 mRNA表达的影响

目的:观察复方蒲黄颗粒(PH)对局灶性脑缺血再灌注大鼠神经元凋亡的影响,并探讨其作用机制。方法:采用大脑中动脉线栓法建立局灶性脑缺血再灌注大鼠模型。75只大鼠分为假手术、模型和PH高、中、低剂量组。采用Nissl染色观察神经元形态变化,TUNEL法检测神经元凋亡,原位杂交检测Caspase-3mRNA的表达。结果:PH高、中剂量组少量细胞核固缩深染,细胞丢失、凋亡细胞数及Caspase-3mRNA阳性细胞数均显著减少。结论:PH可下调Caspase-3的表达,从而抑制神经元凋亡,对脑缺血再灌注损伤有保护作用。     

Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.     

Phosphodiesterase inhibitors in airways disease

Phosphodiesterases hydrolyse intracellular cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into inactive 5' monophosphates, and exist as 11 families. They are found in a variety of inflammatory and structural cells. Inhibitors of PDEs allow the elevation of cAMP and cGMP which lead to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation or of immune responses. PDE4 inhibitors specifically prevent the hydrolysis of cAMP, and PDE4 isozymes are present in inflammatory cells. Selective PDE4 inhibitors have broad spectrum anti-inflammatory effects such as inhibition of cell trafficking, cytokine and chemokine release from inflammatory cells, such as neutrophils, eosinophils, macrophages and T cells. The second generation PDE4 inhibitors, cilomilast and roflumilast, have reached clinical trial stage and have some demonstrable beneficial effects in asthma and chronic obstructive pulmonary disease (COPD). The effectiveness of these PDE4 inhibitors may be limited by their clinical potency using doses that have minimal effects on nausea and vomiting. Topical administration of PDE4 inhibitors may provide a wider effective to side-effect profile. Development of inhibitors of other PDE classes, combined with PDE4 inhibition, may be another way forward. PDE5 is an inactivator of cGMP and may have beneficial effects on hypoxic pulmonary hypertension and vascular remodelling. PDE3 and PDE7 are other cAMP specific inactivators of cAMP. PDE7 is involved in T cell activation and a dual PDE4-PDE7 inhibitor may be more effective in asthma and COPD. A dual PDE3-PDE4 compound may provide more bronchodilator and bronchoprotective effect in addition to the beneficial PDE4 effects.