淀粉样前体蛋白(APP)分泌的神经及药物调节

综述了多种神经递质通过兴奋受体参与APP的分泌过程。这些受体包括M1、M3、5 HT2 、5 HT1C,代谢型谷氨酸受体及肽能加压素和缓激肽受体。脑片实验同样表明内源性神经递质和神经调质可调节APP在哺乳动物脑中的代谢。进一步明确神经递质在AD中的作用 ,有利于研究开发出更多的针对不同受体亚型或递质系统的药物 ,使AD的治疗途径进一步拓宽     

5-羟色胺及其受体与阿尔茨海默病的关系

5-羟色胺(5-hydroxytryptamine,5-HT)是一种重要的单胺类神经递质,其功能异常可能与包括阿尔茨海默病(Alzheimer disease,AD)在内的神经系统疾病密切相关。许多研究结果表明,5-HT受体在数量和分布等方面所发生的变化与AD的发生发展有关。本文就近年来5-HT与AD之间关系的研究进展进行综述,为药物治疗AD提供新思路。     

治疗阿尔茨海默病的药物研究进展

阿尔茨海默病（AD）是一种以进行性的,不可逆转的认知能力下降、记忆能力下降和精神行为异常为临床表现的神经系统退行性疾病。目前,AD 没有早期发现的医学手段,临床症状发生时,病理改变已经发生了几年甚至几十年,所以待临床症状发生后确诊,患者的生存期只余下6~10年。随着世界人口的日益老龄化,解决阿尔茨海默病的治疗问题迫在眉睫。目前治疗该病的药物有作用于神经递质及受体的药物、神经保护剂、抑制β-淀粉样蛋白生成或聚集的药物、降低 tau 蛋白过度磷酸化的药物等。本文从 AD 的各种可能的发病机制出发,介绍目前临床常用治疗 AD 的药物的种类及其研究进展,以期为临床用药提供更全面的参考。     

阿尔茨海默病的血管危险因素及其药物治疗

除了已知的遗传、β淀粉样蛋白沉积、神经递质异常、Tau蛋白异常磷酸化等因素外,腩血管病变等血管危险因素(VRF)在阿尔茨海默病(AD)的发病过程中也起着重要的作用.但VRF对AD发病机制的具体影响尚未阐明.本文根据目前该领域最新研究对VRF在AD发病过程中的作用做一综述,以期阐明VRF诱发AD的各种可能机制以及其他各诱发因素之间的关系.     

β淀粉样蛋白靶向药物治疗阿尔茨海默病的研究进展

以调节神经递质为主的阿尔茨海默病(AD)治疗药物,虽能缓解症状,但难以逆转疾病进展.近期药物的研发重点主要聚焦于能有效延缓疾病进程及预防AD发生的药物,其中以β淀粉样蛋白(Aβ)为靶点的药物开发得到了较为广泛的研究.本文综述近年针对Aβ的AD药物研究进展.     

GABAB与NMDA受体对糖尿病神经病变形成的研究进展

近年来研究证实:GABAB受体作为一种与G蛋白相偶联的受体,调控海马、丘脑、脊髓等神经系统抑制性/兴奋性神经递质的释放[1-3],其下调可促进糖尿病周围神经痛形成[2]。谷氨酸作为兴奋性神经递质激活NMDA受体,可触发一系列钙依赖性第二信使级联反应,这一机制在糖尿病神经痛的形成过程中也发挥重要作用[4]。     

CCR3的缺失导致阿尔茨海默病小鼠模型中β-淀粉样蛋白和过度磷酸化tau蛋白的减少

目的慢性神经炎症可能参与阿尔茨海默病(AD),其特征在于,神经胶质细胞活化和促炎性细胞因子和趋化因子的分泌。趋化因子CCL11已被证明是衰老过程中认知衰退的致病因素,但它是否参与AD的发病却很少被我们所知。在本研究中,我们拟在小鼠模型中回答CCL11及其受体CCR3是否参与AD发病过程的问题。方法我们采用了免疫组化、蛋白印迹和体视学细胞计数等方法来回答上述问题。结果 CCL11特异性受体CCR3的缺失使APP/PS1双转基因小鼠脑内tau蛋白磷酸化,Aβ沉积以及小胶质细胞及星形胶质细胞增生显著降低。结论 CCL11的增加可能是AD的危险因素,并且拮抗CCR3可能给AD带来治疗益处。     

趋化因子参与阿尔茨海默病的研究进展

趋化因子在阿尔茨海默病(Alzheimer's disease,AD)的发病机制中发挥多重作用。AD是一种中枢神经系统的慢性炎症性疾病,其神经病理学特征包括神经原纤维缠结(neurofibrillary tangles,NFT)、β淀粉样蛋白(amyloid beta protein,Aβ)斑块、神经炎症和神经元突触丢失。趋化因子通过激活或调节炎症细胞和神经胶质细胞参与AD的病理机制,发挥了促炎和抗炎双重作用。AD患者血清、脑脊液和脑组织中的趋化因子水平发生相应的变化。该综述总结了趋化因子及其受体在AD中的生物活性以及变化规律,为临床治疗AD提供新的策略。     

阿尔茨海默病与Nogo/NgR

阿尔茨海默病（AD）是慢性进行性中枢神经系统变性病,目前认为β-淀粉样蛋白（Ap）的沉积是AD的重要致病原因。最近的研究发现,内质网膜蛋白（RTN）家族成员Nogo及其受体NgR也参与了AD的病理发生过程。Nogo最初被发现是位于中枢神经系统（CNS）少突胶质细胞膜上,可通过神经元上的受体NgR介导信号传递,抑制神经元突起生长。     

B型肉毒毒素受体

美国威斯康星大学 ( UWI)的研究者已发现肉毒毒素如何阻止神经元中的神经递质释放 ,但尚不知毒素如何首先进入神经元。不管是吸入还是注入 ,毒素直接朝向神经元。毒素通过与神经元表面的受体结合 ,能被带入细胞 ,进而阻止神经递质的释放。　　UWI的研究者发现神经节苷脂和蛋白一起作为受体起作用。应用细胞模型 ,研究者确认了与神经节苷脂一起作为 B型肉毒毒素受体的两种蛋白 ,它们是发现于某型神经元中的突触结合蛋白 ( syt) 和 。　　当其中一种蛋白伸出细胞外时 ,毒素能锁定其上并被内化。为了进一步证实这一蛋白 -脂质对是毒素的目…     

中药提取成分抗阿尔茨海默病研究进展

随着世界人口的老龄化,阿尔茨海默病的发病率不断上升,严重威胁着人类健康和社会发展。关于其发病机制仍不清楚,目前认为与神经递质紊乱、基因突变、自由基损伤、神经细胞凋亡、淀粉样β蛋白沉积和tau蛋白异常磷酸化等有关。近年有关中药及其提取物防治阿尔茨海默病的研究日益受到重视,并取得了重大进展。本文对近几年来国内外关于中药提取成分抗阿尔茨海默病的研究进展进行综述。     

Clinical data and animal studies on adaptive receptor changes occurring in depression and after antidepressive treatment: A hypothesis of antidepressive action

The clinical and animal studies on the effects of antidepressant treatments on receptor-related changes in the functioning of central neurotransmitter systems, are reviewed. The great variability in individual clinical responses make it impossible to formulate one coherent hypothesis about adaptive receptor changes occurring in human beings. Nevertheless, it is concluded that neuroadaptive responses found in the catecholaminergic systems (dopaminergic and adrenergic alpha-1 receptors) might be important as the underlying mechanism for therapeutic efficacy in depression of antidepressant drugs (AD) and electroconvulsive shock treatment (ECS). The animal studies conducted in our laboratory over the last decade provide evidence for the existence of limbic neurotransmitter modulatory mechanism of action of AD and ECS. It is suggested that at least in the limbic areas (i.e. in the hippocampus and nucleus accumbens, the main structures of the mesolimbic system), AD and ECS produce bidirectional effects. On the one hand they were found to reduce ‘inhibitory’ signals mediated through serotonergic, GABA-ergic and alpha-2 adrenergic receptors while on the other hand they enhanced ‘excitatory’ central processes mediated via the dopaminergic and adrenergic alpha-1 receptors. Confirmation of this hypothesis was obtained from behavioral experiments (locomotor and exploratory activity), consisting of microinjections of selective receptor agonists and antagonists into the hippocampus and nucleus accumbens, following the chronic administration of different AD's and ECS. We propose, therefore, that the mechanism of action of antidepressant therapies should be considered from the anatomical and receptor viewpoint, the crucial element being the ‘tuning’ of the signals within the limbic areas. The consequence of this mechanism is an enhancement of these processes which can be defined as ‘activatory’, in terms of their mood elevating effects. The final effect of antidepressant therapy emerges as a result of transmitter interactions and disinhibitory processes. The ‘limbic modulatory neurotransmitter mechanism’ is thus suggested to be responsible for the effect of antidepressant treatment.     

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review

Alzheimer's disease (AD) is a chronic age-related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability of an individual. The exact pathophysiology of AD is not fully understood. However low level of the neurotransmitter named acetylcholine (ACh), aggregation of Aβ peptide into toxic Aβ plaque, hyperphosphorylation of tau, bio-metal imbalance, and oxidative stress are the main hallmarks of this disease. Due to the complex pathophysiology of AD, no specific treatment is available in the market, and treatment is only limited to the symptomatic relief. So, there is an urgent need for the development of new drug candidate, which can have disease-modifying effect and improve learning and memory in AD patient. Therefore, berberine-based multifunction compounds with potential cholinesterase inhibitory properties were reviewed in this article. Structure–activity relationship (SAR) and biological activity provide highlights on the new derivatives used for the management of AD.     

Cross-talk between oxidative stress and modifications of cholinergic and glutaminergic receptors in the pathogenesis of Alzheimer＇s disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its pathogenesis is likely to be associated with multiple etiologies and mechanisms in which oxidative stress and deficits of neurotransmitter receptors may play important roles. It has been indicated that a high level of free radicals can influence the expressions of nicotinic receptors (nAChRs), muscarinic receptors (mAChRs), and N-methyl-D-aspartate (NMDA) receptors, exhibiting disturbances of cellular membrane by lipid peroxidation, damages of the protein receptors by protein oxidation, and possible modified gene expressions of these receptors by DNA oxidation. nAChRs have shown an antioxidative effect by a direct or an indirect pathway; mAChR stimulation may generate reactive oxygen species, which might be a physiological compensative reaction, or improve oxidative stress; and high stimulation to NMDA receptors can increase the sensitivity of oxidative stress of neurons. This review may provide complemental information for understanding the correlation between oxidative stress and changed cholinergic and glutaminergic receptors in AD processing, and for revealing the underlying molecular mechanisms of these factors in the multiple etiologies and pathophysiology of the disorder.     

Development of new Alzheimer's disease drug candidates using donepezil as a key model

Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by β-amyloid precipitation, β-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aβ aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.     

治疗阿尔茨海默病药物的研究进展

阿尔茨海默病(AD)为中枢神经退化性疾病,是危害人类健康的一大综合征,治疗AD药物是近年来研究的一大热点.综述了近5年来治疗AD药物的研究进展,根据作用机制的不同对临床应用的抗AD和有促智活性的药物进行分类详述,主要分为乙酰胆碱酯酶抑制剂等改善胆碱功能的药物、M1受体激动剂、抗氧化药物、消炎镇痛药物、抑制Aβ蛋白形成的药物、神经生长因子、钙调节剂、晚期糖基化终产物(AGE)抑制剂以及中药复方等几类.     

New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease

As the population ages, Alzheimer’s disease (AD), the most common neurodegenerative disease in elderly people, will impose social and economic burdens to the world. Currently approved drugs for the treatment of AD including cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartic acid receptor antagonist (memantine) are symptomatic but poorly affect the progression of the disease. In recent decades, the concept of amyloid-β (Aβ) cascade and tau hyperphosphorylation leading to AD has dominated AD drug development. However, pharmacotherapies targeting Aβ and tau have limited success. It is generally believed that AD is caused by multiple pathological processes resulting from Aβ abnormality, tau phosphorylation, neuroinflammation, neurotransmitter dysregulation, and oxidative stress. In this review we updated the recent development of new therapeutics that regulate neurotransmitters, inflammation, lipid metabolism, autophagy, microbiota, circadian rhythm, and disease-modified genes for AD in preclinical research and clinical trials. It is to emphasize the importance of early diagnosis and multiple-target intervention, which may provide a promising outcome for AD treatment.     

The role of the endocannabinoid system in Alzheimer's disease: facts and hypotheses

Unlike other neuroinflammatory disorders, like Parkinson's disease, Huntington's disease and multiple sclerosis, little is still known of the role of the endocannabinoid system in Alzheimer's disease (AD). This is partly due to the poor availability of animal models that are really relevant to the human disease, and to the complexity of AD as compared to other neurological states. Nevertheless, the available data indicate that endocannabinoids are likely to play in this disorder a role similar to that suggested in other neurodegenerative diseases, that is, to represent an endogenous adaptive response aimed at counteracting both the neurochemical and inflammatory consequences of beta-amyloid-induced tau protein hyperactivity, possibly the most important underlying cause of AD. Furthermore, plant and synthetic cannabinoids, and particularly the non-psychotropic cannabidiol, might also exert other, non-cannabinoid receptor-mediated protective effects, including, but not limited to, anti-oxidant actions. There is evidence, from in vivo studies on beta-amyloid-induced neurotoxicity, also for a possible causative role of endocannabinoids in the impairment in memory retention, which is typical of AD. This might open the way to the use of cannabinoid receptor antagonists as therapeutic drugs for the treatment of cognitive deficits in the more advanced phases of this disorder. The scant, but nevertheless important literature on the regulation and role of the endocannabinoid system in AD, and on the potential treatment of this disorder with cannabinoids and endocannabinoid-based drugs, are discussed in this mini-review.     

Alzheimer's disease: pathophysiology and pharmacotherapy

Alzheimer's disease (AD) is the leading cause of dementia in mid-to-late life, and is estimated to afflict approximately 20 million people worldwide. There are considerable financial, social and emotional costs associated with the burden of caring for patients with AD. Clinically, AD is characterized by an insidious loss of memory, associated functional decline and behavioral disturbances. Many neurotransmitter systems are also affected; however, degeneration in the cholinergic system occurs earlier and more consistently than in other systems. As cholinergic function is required for short-term memory function, it is believed that the cholinergic deficit in AD is also responsible for much of the short-term memory deficit. The cholinergic hypothesis of AD has led to the development of a number of strategies to enhance the failing cholinergic neurons and thus the neurotransmitter acetylcholine (ACh). In general, appropriate management of AD patients with antioxidants, acetylcholinesterase inhibitors (AChEIs) and psychotropic agents can slow the progression of the disease, improve cognition, and reduce behavioral disturbances, which may enhance patient and caregiver quality-of-life and delay nursing home residence.