阿尔茨海默病防治药物靶标的研究进展*

阿尔茨海默病（Alzheimer＇s disease，AD）是发生于老年期或老年前期的一种慢性进行性退化性脑变性疾病，以记忆减退、认知障碍为主要特征。由于其发病机制复杂，涉及多系统、多环节结构与功能异常，因此迄今尚无理想的防治药物间世。药物靶标的发现和选择是药物研发成功的重要前提，近年来，AD发病机制研究的不断深入为AD防治药物的筛选和研究提供了新的靶标。现简要综述近年来针对AD发病机制的药物靶标的研究进展。     

硫酸乙酰肝素多糖类似物的抗乳腺癌活性研究进展*

硫酸乙酰肝素（heparan sulfate，HS）参与乳腺癌发生和发展的多个环节，随着HS对细胞生长因子调节机制研究的深入，HS多糖类似物的研发已经成为当前研究的热点。现综述HS结构及在乳腺癌发生发展中的作用和机制、HS多糖类似物的分类、天然产物中提取的多糖和化学修饰的多糖衍生物的抗癌活性及构效关系的研究进展。     

白藜芦醇在阿尔茨海默病防治中作用机制研究进展

白藜芦醇是一种广泛存在于葡萄、虎杖、花生、桑葚、决明子等植物中的多酚类化合物,具有广泛的生物学活性,如抗衰老、抗炎、抗氧化、清除自由基、调节自噬、抗凋亡、雌激素样作用等。近几年的深入研究表明,白藜芦醇可透过血脑屏障,对神经系统具有保护作用,可用于防治阿尔茨海默病。基于此,本文以阿尔茨海默病相关发病机制（如β-淀粉样蛋白聚集、tau蛋白异常磷酸化、神经炎症、氧化应激）为出发点,对白藜芦醇在阿尔茨海默病模型的相关研究进行归纳总结,为深入开发白藜芦醇的药用潜能提供参考资料。     

生物活性多糖在防治阿尔茨海默病中的作用

阿尔茨海默病(AD)主要表现为认知功能障碍和记忆障碍,是一种中枢神经系统退化性疾病,发病机制复杂,目前临床尚未有能彻底治愈的有效药物。AD的病理学特征主要为脑细胞外β-淀粉样蛋白(Aβ)沉积形成的老年斑(SP),脑细胞内高度磷酸化的tau蛋白形成神经元纤维缠结(NFT)。AD病因及分子机制十分复杂,至今尚不明确,其中Aβ级联假说、自由基学说和Tau蛋白异常磷酸化学说占主要地位。目前临床上治疗AD主要以西药为主,但具有毒性大、易耐药等局限性。研究发现,中药及其有效成分如多糖具有改善学习记忆能力、抗Aβ沉积、抗NO诱导的神经毒性、抗氧化应激、抗自由基损伤、抗炎症和抑制神经细胞凋亡等多方面的作用,使其可以从多靶点的角度来对AD进行防治。多糖具有广泛的生物活性,越来越多的研究证据显示,多糖对AD的防治也具有一定的积极作用。本文详细综述了微生物多糖、植物多糖和动物多糖防治AD方面的药理作用及其机制研究进展。微生物多糖:保护神经细胞和突触,AD早期海马和内嗅皮质区域会出现神经元和突触的缺失,因此保护神经细胞和突触对于AD的治疗具有重要作用。灵芝多糖高、中剂量组能明显提高AD大鼠学习记忆能力,其提高大鼠记忆能力的作用可能是通过升高AD大鼠海马内降低的突触素/突触来实现的。植物多糖:(1)清除自由基、抗氧化,在AD发生发展过程中Aβ与氧化应激关系密切,Aβ可通过多种途径产生过氧化物和自由基,从而加剧过氧化作用对神经细胞的损伤。例如肉苁蓉多糖能明显升高AD大鼠脑组织超氧化物歧化酶(SOD)活性,降低脑内丙二醛含量,使脑内的氧自由基减少,所以肉苁蓉多糖提高AD大鼠的学习记忆能力,可能是通过减少氧自由基的损伤、加速体内自由基的清除以及抑制海马神经元的凋亡来实现的。(2)改善tau蛋白过度磷酸化,tau蛋白过度磷酸化导致NFT形成的主要原因之一,也是痴呆发病的重要机制之一。例如山茱萸多糖可通过抑制p-tau(Ser422)和p-tau(Ser396)生成,改善AD大鼠学习记忆能力。(3)抑制细胞凋亡,细胞凋亡与AD的发生、发展关系密切,AD患者大脑皮质和海马区的神经元丢失与神经细胞凋亡密切相关。所以通过抑制神经细胞凋亡延缓AD的病程进展。(4)改善能量代谢,脑组织神经细胞能量代谢障碍如葡萄糖代谢降低是AD患者的一个重要病理特征,因此改善脑组织的能量代谢障碍是目前抗痴呆的一个策略。宁夏枸杞多糖可通过缓解脑内葡萄糖代谢障碍从而改善衰老状态。动物多糖:改善中枢胆碱能系统,乙酰胆碱(ACh)是脑组织内重要的神经递质,脑内细胞外液中ACh的变化与认知功能的改变具有密切关系。综上所述,多糖具有防治阿尔茨海默病的作用,在抗AD药物开发方面有良好的应用前景。     

Reelin蛋白在阿尔茨海默病中的研究进展

Reelin作为分泌型基质外糖蛋白,在神经发育早期以及成熟后的大脑中都有重要作用。近年来研究表明,包括阿尔茨海默病、精神分裂症、双相情感障碍等在内的多种神经精神疾病中,都出现了Reelin蛋白的异常表达。该文主要对Reelin蛋白的结构功能及所属通路在阿尔茨海默病发病机制中的作用进行综述。     

Aβ受体在阿尔茨海默病中的研究进展

阿尔茨海默病(AD)是一种进行性神经退行性疾病,β淀粉样蛋白(Aβ)沉积是AD主要病因之一.Aβ引发神经元损伤的最主要原因可能是通过与细胞膜上的Aβ受体结合进而引起下游信号通路改变,直接损伤神经元或增加神经元的易感性.目前,Aβ受体和转运体主要包括:PirB、FcγRⅡB、PrPc、NgR1、EphB2、p75NTR、...     

低分子肝素制备的研究进展

肝素作为一种有效的抗凝药物广受关注,但其在使用过程中出现的各种副作用使人们的目光转向了低分子肝素(LMWH)。LMWH具有更高的安全性、更好的皮下注射药物动力学、更长的半衰期和更好的生物利用度。本文阐述了LMWH的各种制备方法,探讨了LMWH制备的发展趋势,为LMWH研究者选择适当的制备方法提供参考。     

阿尔茨海默病发病机制研究进展

阿尔茨海默病(AD)病因及发病机制尚未完全阐明,有关其发病机制有β-淀粉样蛋白级联假说、Tau蛋白假说、神经血管学说和氧化应激学说等多种.本文就现有较公认的发病机制研究进展作一综述.     

国内低分子肝素制剂研究进展

目的概述近几年来国内报道的低分子肝素 (LMWH)制剂的研究进展。方法通过查阅 1980～ 2 0 0 2年中国生物期刊文摘库 (CBA) ,对有关LMWH的制剂进行分析。结果与结论LMWH的制剂目前有注射剂、胶囊剂、舌下含片、软膏剂、凝胶剂、喷雾剂及栓剂等     

红景天苷防治阿尔茨海默病作用机制的研究进展

阿尔茨海默病是最常见的老年进行性神经退行性疾病,药物治疗是阿尔茨海默病最常用的治疗手段,目前临床上只有少数药物获批。红景天苷是红景天中的主要活性成分,能够通过降低β淀粉样蛋白的神经毒性、抑制神经细胞凋亡、减轻神经细胞氧化应激和炎性损伤、延缓神经元衰老、保护线粒体功能等多种机制发挥防治阿尔茨海默病的作用。因此综述了红景天苷防治阿尔茨海默病的作用机制,为红景天苷的临床研究提供参考。     

阿尔茨海默病的治疗药物作用机制研究进展

阿尔茨海默病的发病机制复杂,多数学者认为β-淀粉样蛋白级联反应、Tau蛋白过度磷酸化是导致该病发生发展的主要原因。目前该病的治疗药物如乙酰胆碱酯酶抑制剂（多奈哌齐、利斯的明、加兰他敏、石杉碱甲）和非竞争性N-甲基-D-天冬氨酸受体拮抗剂（美金刚）均以改善症状为主,尚无能延缓或终止疾病进展的药物。近年来国内外进行了大量以Aβ、Tau蛋白为靶点的治疗药物研究。主要对阿尔茨海默病治疗药物的研究进展进行综述。     

白藜芦醇治疗阿尔茨海默病的研究进展

神经退行性疾病是一种慢性进展性疾病,其特点是中枢神经系统神经元的逐渐丧失。由于血脑屏障的存在,经典的抗炎药物如类固醇激素和非甾体类抗炎药,对神经系统疾病的治疗作用有限。因此,开发新的抗炎药物,对于预防和治疗神经系统疾病具有重要的意义。白藜芦醇是一种有很强活性的天然多酚类物质,目前研究已显示其具有心血管保护、神经保护、免疫调节、肿瘤的化学预防作用。近年来还发现其具有抗神经炎症作用,可用于治疗神经精神性疾病,如帕金森病、阿尔茨海默病(AD)和亨廷顿症等。综述白藜芦醇对AD的保护作用及其机制研究进展,为进一步推进白藜芦醇用于防治AD的研究提供参考。     

Vaccination for the prevention and treatment of Alzheimer's disease

In vitro studies showed that beta-amyloid peptide neurotoxicity correlates with the formation of fibrillar beta-amyloid and the variation in neurotoxic potency is related to the extent of peptide aggregation. Many efforts are being focused on the development of potent and selective inhibitors of amyloid formation in order to reduce the extent of their deposition and related neurotoxic effects. In our laboratory we are pioneering the idea that site-directed monoclonal antibodies (MAbs) can solubilize synthetic beta-amyloid aggregates. Production and performance of such antibodies by repeated injections of toxic human beta-amyloid fibrils into transgenic mice suggests the feasibility of vaccination against Alzheimer's disease (AD). Here we report the development of a novel immunization procedure for the production of effective antiaggregating beta-amyloid antibodies. The antigen is built from filamentous phages displaying the only four amino acids EFRH located at positions 3-6 of the beta-amyloid peptide found to be the main regulatory site of amyloid formation. Autoimmune antibodies are obtained by EFRH phage administration in guinea pigs, which exhibit human identity in the beta-amyloid peptide region. Availability of such antibodies opens up possibilities for the development of an efficient and long-lasting immunization procedure for the treatment of AD.     

Role of oestrogen in the treatment and prevention of Alzheimer's disease

Alzheimer's disease (AD), the most common primary dementing disorder, results in devastating clinical and socio-economic consequences, and is a leading cause of death among the elderly. Despite recent advances in the neurobiology of AD, identification of effective treatment strategies has remained frustratingly elusive. Administration of currently available cholinergic drugs improves symptoms in some patients with AD, but may be associated with efficacy-limiting adverse effects. Moreover, it is not yet known whether cholinergic drugs have the potential to alter the progression of AD pathology. In contrast, cumulative evidence from basic neuroscience and clinical research demonstrates that oestrogen has significant neuromodulatory and neuroprotective properties. Furthermore, preliminary evidence from clinical studies indicates that oestrogen replacement therapy can significantly enhance cognitive function in postmenopausal women with AD, and reduce the risk for developing the disease. However, long-term administration of oestrogen is associated with potentially serious adverse effects, including increased risk for developing malignancies of the uterus and the breast. Fortunately, tissue-specific analogues of oestrogen are in development that could specifically target the functions of the brain, and may be devoid of the cancer-inducing and feminising properties of the hormone. Availability of these analogues will make it feasible to treat AD with oestrogen in both women and men. However, findings of preliminary studies, although promising, need to be confirmed in larger, controlled clinical trials before the role of oestrogen in the treatment and prevention of AD can be firmly established.     

阿尔茨海默症治疗药物的研究进展

阿尔茨海默病(Alzheimer′s disease,AD)是一种常见的进行性神经退行性疾病,它严重影响着老年人的健康,对社会造成巨大的压力。但是由于其发病机制不明确,临床治疗效果不佳。近年来,针对AD的治疗方法层出不穷,本文就目前的研究进展进行综述。     

Herbal medicines for the prevention and treatment of Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of progressive dementia in aging. Research on AD therapy has been partly successful in terms of developing symptomatic treatments, but there have been a number of failures with regard to developing disease-modifying therapies. The pathogenesis of AD remains unclear and the present one-drug, one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. This review briefly introduces progress in the development of anti-AD treatments and then focuses on recent advances in the research, characteristics, and development of herbal medicines. Because AD arises via multiple pathological or neurotoxic pathways, herbal medicines have the potential to be developed into optimum pharmaceuticals and nutraceuticals for AD because of their multi-function, multi-target characteristics.     

秀丽隐杆线虫模型在阿尔茨海默病研究中的应用

阿尔茨海默病(Alzheimer s disease,AD)是一种与衰老相关的神经退行性疾病,以Aβ沉积和Tau蛋白过度磷酸化为主要病理特征。秀丽隐杆线虫以其神经系统结构简单、遗传信息清晰等优势而作为一种AD研究的模式生物,尤其是人源Aβ1-42和Tau转基因线虫(CL2006/P301L)已被广泛应用。本文简述秀丽隐杆线虫及其AD模型,总结近几年应用模型线虫研究AD病理机制的文献,为进一步筛选治疗AD的药物提供可靠的线索和思路。     

Muscarinic agonists for the treatment of Alzheimer's disease: progress and perspectives

Much interest has focused on the development of selective muscarinic agonists for the treatment of Alzheimer's disease (AD). Cholinergic replacement therapy is thought to be beneficial in alleviating some of the cognitive dysfunctions in this disorder. The cholinergic neuronal tracts are involved in memory and learning processes, and the extent of the degeneration of the cortical projections correlates with the severity of the dementia. An M1 selective muscarinic agonist may be effective in treating at least some of the cognitive symptoms in AD. Highly selective M1 agonists, producing cellular excitation, should be beneficial in AD, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex or hippocampus. Functional abnormalities in AD may also occur along various signal transduction pathways mediated, in part, at least, by muscarinic receptors. In general, activities associated with mAChR subtypes and m1 receptors, in particular, indicate that M1 agonists may also be useful for this aspect of AD. Mismetabolism of amyloid precursor proteins (APPs) may induce AD. Recent studies indicate that the formation of the b-amyloid peptide (Abeta) and amyloid plaques is linked to the loss of cholinergic function in AD. New data on the activation of m1 mAChRs in conjunction with recent findings that the induction of such receptors stimulates neurotrophic-like activities, decreases tau phosphorylation and inhibits apoptosis indicate that restoring the cholinergic tone in AD may be useful both in improving memory function and in altering the onset and progression of AD dementia. This article focuses on the recent, promising developments in this field and assesses the value of muscarinic agonists currently under development for the treatment of AD.     

多糖铁复合物及其治疗肾性贫血的研究进展

肾性贫血的主要原因是促红细胞生成素不足,而且缺乏铁会影响红细胞生成。多糖铁复合物是一种副作用小、稳定性好的口服补铁剂,具有良好的生物利用度,能够有效提高贫血患者的血红蛋白水平。本文对多糖铁复合物的结构性质、作用机制、临床应用现状及进展作一综述。