神经退行性疾病、胃肠动力异常和肠道菌群失调相互关系的研究进展

阿尔茨海默病(AD)、帕金森病(PD)和多发性硬化症(MS)是常见的神经退行性疾病,往往伴随胃肠道动力异常和肠道菌群失调。肠道菌群已被证明通过神经内分泌系统以及神经免疫系统调控大脑功能,进而影响神经退行性疾病的发生发展。一些神经退行性疾病患者被确诊前就存在胃肠道功能失调,而肠道菌群与胃肠动力异常关系密切,提示肠道菌群也可能通过肠道神经系统影响神经退行性疾病。本文综述了肠道菌群通过神经内分泌-神经免疫互作参与介导胃肠道动力异常的神经退行性疾病的研究进展。     

自噬在神经突起变性过程中的作用

自噬是细胞内物质的降解途径之一,介导长寿命蛋白和部分细胞器的降解,对维持神经元内环境稳态具有重要的生理功能。蛋白质聚集体在神经元内外的堆积是多种神经系统退行性疾病的共同病理表现。神经元轴突和树突(或统称"突起")细长,因而对蛋白质聚集和细胞内受损细胞器的堆积尤为敏感。神经系统退行性疾病发病早期,常伴随突触病变、轴突末梢变性和突起萎缩等病理现象。因此,通过自噬途径有效清除蛋白聚集物和受损细胞器,可能可以缓解神经突起的变性。然而也有研究表明,自噬不足或过度活化也将加剧神经突起损伤。本文介绍了神经突起中自噬的相关研究进展,包括神经突起中自噬的形成和运输,自噬对神经突起生长和损伤的调控,及自噬与神经系统退行性疾病中突起损伤的相关性。     

白藜芦醇抗神经退行性疾病的研究进展

白藜芦醇是一种多酚类化合物,广泛存在于蔬菜、水果、茶叶等植物中。现代药理学研究证明,白藜芦醇具有抗炎、抗氧化应激及抗凋亡等作用,并能使神经退行性病变的危险降低,如帕金森病、阿尔采末病和杭廷顿病等。近年来,白藜芦醇对神经退行性疾病的保护作用及其机制研究日益增多,本文结合国内外对白藜芦醇的研究报道,综述白藜芦醇用于防治神经退行性疾病的研究进展。     

细胞骨架与神经退行性疾病

神经退行性疾病(Neurodegenerative disease)是一种以神经元退行性病变为基础的慢性进行性神经系统疾病,其病因十分复杂,其中线粒体功能障碍学说、氧化应激学说、蛋白质发生错误折叠聚集、炎症、免疫功能缺陷,基因突变等已经得到普遍认可。近年来的研究发现,细胞骨架在神经元变性过程中发挥了重要作用。细胞骨架是细胞质内蛋白质丝组成的纤维网架体系,其决定和维持着细胞的形态结构,同时参与细胞运动、分裂、胞浆运输等生命活动,对信号传导具有重要的意义。该文就其在神经退行性疾病方面的研究进行综述。     

神经退行性疾病状态下血-脑屏障变化机制及中药对血脑屏障的影响研究进展

血-脑屏障（BBB）结构和功能的完整性是维持中枢神经系统动态平衡的关键因素。BBB异常伴随神经退行性疾病的发展过程,不同的神经退行性疾病,其BBB异常的病理机制不同,而药物对BBB异常的改善作用也严重影响药物对神经退行性疾病的疗效。本文主要针对神经退行性疾病状态下BBB异常的分子机制及中药的调控作用及其机制两方面进行综述,为神经退行性疾病靶向血脑屏障药物的研发提供基础理论参考     

银杏叶提取物对神经退行性疾病的作用机制及研究进展

随着人口老龄化的加快,神经退行性疾病的发病率呈逐年上升的趋势。神经退行性疾病具有病因复杂、病程长、难治愈等特点,目前银杏叶提取物的神经保护作用已被广泛认可,但其有效成分及其具体作用机制尚未明确。本文将根据神经退行性疾病的发病机制来探讨银杏叶提取物对神经的保护作用,主要从其改善Aβ聚集、抗炎、抗氧化、抗凋亡、保护线粒体、调节能量代谢等角度来研究其治疗神经退行性疾病的机制。     

秀丽隐杆线虫用于帕金森病及其治疗药物的分子生物学研究

帕金森病是一种常见的神经退行性疾病,利用脊椎动物模型和组织培养系统可对神经退行性疾病病理进行有价值的研究,但帕金森病及其治疗药物的病理、药理分子机制研究尚待深入.本文阐述如何利用线虫的遗传学和神经生物学特点对帕金森病及治疗药物进行研究和评价.     

以α-synuclein为靶点的抗帕金森病药物研究进展

帕金森病(Parkinsons disease,PD)是常见的神经退行性疾病,目前对PD的药物治疗仅限于改善症状,尚缺乏能够延缓疾病进程并具有神经保护作用的药物。α-突触核蛋白(α-synuclein,α-syn)是一种位于神经元突触前末端、由140个氨基酸组成的蛋白质,它的突变、聚集和过度积累与包括PD在内的一系列神经退行性疾病密切相关。开发针对α-syn及其相关靶点的药物,可能是控制PD等突触核蛋白病进程的有效途径。该文主要从抑制α-syn表达和聚集、促进其解聚和降解、调节其修饰状态等方面,对以α-syn为靶点的药物研究进展进行综述。     

海洋抗神经退行性疾病候选药物GTS-21及其类似物的研究进展

α7烟碱型乙酰胆碱受体(α7nAChR)主要分布在海马和相关皮层,与老年斑的沉积部位一致,且对钙离子有相当高的通透性,可以调节钙的活化及递质乙酰胆碱的释放,能直接影响认知和记忆功能,因此逐渐成为阿尔茨海默症等神经退行性疾病发病机制的研究热点。GTS-21是由海洋纽形动物类(Nemertea)两孔纽虫(Amphipoius)分泌的毒素新烟碱（Anabaseine）与2 ,4-二甲氧苯甲醛缩合而成的选择性α7nAChR的部分激动剂,作为候选药物被用于治疗阿尔茨海默症及精神分裂症等神经退行性疾病,目前已进入各期临床开发阶段。近年来,为了获得高效、低毒和更易透过血脑屏障的GTS-21衍生物,药物化学家们进行了大量的优化研究,获得了一些具有良好活性的衍生物。本文就GTS-21及其类似物优化的研究进展进行综述。     

模式动物斑马鱼在神经退行性疾病研究中的应用

斑马鱼作为一种新型模式低等脊椎动物,具有发育周期短、体外受精、胚胎透明、突变种多等优势,被广泛应用于神经、心血管、消化等方面的研究中。神经退行性疾病包括帕金森病、阿尔茨海默病等,近年来发病率不断上升,且有年轻化的趋势,严重影响人们的身体健康和生活质量。因其发病机制复杂,至今仍缺乏治疗此类疾病的方法。本文综述近年来用斑马鱼制作神经退行性疾病模型的主要方式及可行性,为研究神经退行性疾病中斑马鱼模型的选择提供参考。     

The role of the ATP-binding cassette transporter P-glycoprotein in the transport of β-amyloid across the blood-brain barrier

The blood-brain barrier (BBB) protects the brain against endogenous and exogenous compounds and plays an important part in the maintenance of the microenvironment of the brain. In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ). There is growing evidence that the ABC transport protein P-glycoprotein (P-gp), a major component of the BBB, mediates the efflux of Aβ from the brain. In this review, we discuss the possible role of P-gp in Alzheimer's disease and other neurodegenerative disorders, and consider how a fuller understanding of this function might promote the development of more effective treatment strategies.     

Neuronal apoptosis as a therapeutic target in neurodegenerative disease

Apoptosis is a form of physiological or programmed cell death. It has been speculated that this process might account for the death of selective neuronal populations in certain progressive neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) and some circumstantial evidence to support this view has been forthcoming. Increased understanding of the molecular pathophysiology of neuronal apoptosis may therefore present significant new therapeutic targets, to slow or halt neurodegeneration. This article reviews patents from the last five years which claim the use of apoptotic modulators in neurodegenerative disease. Although there are a significant number of claims, very few are buttressed with strong experimental evidence; this is usually from cell culture studies, rather than animal models of neurodegenerative disease; only a single human clinical study was identified. Thus, although treatment of neurodegenerative disease by means of manipulating apoptosis is an area of much activity and holds promise for the future, clinical application of current patents is unlikely in the near future. Extant medications may conceivably exert some of their action through effects on apoptosis.     

Antioxidants as treatment for neurodegenerative disorders

Oxidative stress is a ubiquitously observed hallmark of neurodegenerative disorders. Neuronal cell dysfunction and cell death due to oxidative stress may causally contribute to the pathogenesis of progressive neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, as well as acute syndromes of neurodegeneration, such as ischaemic and haemorrhagic stroke. Neuroprotective antioxidants are considered a promising approach to slowing the progression and limiting the extent of neuronal cell loss in these disorders. The clinical evidence demonstrating that antioxidant compounds can act as protective drugs in neurodegenerative disease, however, is still relatively scarce. In the following review, the available data from clinical, animal and cell biological studies regarding the role of antioxidant neuroprotection in progressive neurodegenerative disease will be summarised, focussing particularly on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The general complications in developing potent neuroprotective antioxidant drugs directed against these long-term degenerative conditions will also be discussed. The major challenges for drug development are the slow kinetics of disease progression, the unsolved mechanistic questions concerning the final causalities of cell death, the necessity to attain an effective permeation of the blood–brain barrier and the need to reduce the high concentrations currently required to evoke protective effects in cellular and animal model systems. Finally, an outlook as to which direction antioxidant drug development and clinical practice may be leading to in the near future will be provided.     

SMi 4th Annual Conference on Neurodegenerative Disorders: a focus on Alzheimer’s and Parkinson’s disease

This was a small (~ 50 people) focused meeting on neurodegenerative disorders, with most of the speakers being from biotechnology or major pharmaceutical companies. The meeting covered a range of topics including introductions to Alzheimer’s disease and Parkinson’s disease, examples of targeting particular receptors/pathways, animal models and preclinical studies, clinical trial design and the use of biomarkers and imaging modalities. The major focus in the Alzheimer’s disease area was finding symptomatic treatments that are superior to acetylcholinesterase inhibitors and the extensive efforts that are ongoing to develop disease-modifying therapies. In terms of Parkinson’s disease there are now several reports examining the effects of dopamine agonists versus 3,4-dihydroxyphenylalanine on disease progression, and ongoing work with growth factors (e.g., glial cell line-derived neurotrophic factor) and mixed lineage/c-Jun N-terminal kinase inhibitors, such as CEP-1347. Small molecules that enhance endogenous signalling and repair pathways were also discussed.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.     

Psychotic symptoms in Parkinson’s disease: pathophysiology and management

Parkinson’s disease (PD) is a chronic neurodegenerative disease, in which mainly dopaminergic neurons in the substantia nigra in the brain degenerate, leading to a depletion of dopamine (DA) in the striatum. The most important motor disturbances of the disease are bradykinesia (slowing down of movement), hypokinesia (poverty of movement), rigidity (muscle stiffness), tremor and postural instability. Besides these well-known motor symptoms, non-motor symptoms may develop, such as depression, cognitive impairment and psychosis. Psychotic symptoms constitute a relatively common but nevertheless serious complication, with visual hallucinations and paranoid delusions often being most prominent. These symptoms are important contributors to patient and caregiver distress and are often important risk factors for nursing home placement. Exogenous (related to therapeutic interventions) factors are of major importance but endogenous (related to the disease process itself) factors might also contribute to the development of psychotic symptoms in PD. Therapeutic strategies comprise reduction of antiparkinsonian treatment, cholinesterase inhibitors and atypical antipsychotics. As psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of strategies may be chosen.     

Therapeutic strategy at the crossroad of neuroinflammation and oxidative stress in age-related neurodegenerative diseases

Aging is the greatest risk factor for neurodegenerative diseases in the CNS, including two major age-related neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease. Understanding the biology of aging is pivotal in management of patients with neurodegenerative disorders. Genetically programmed aging and oxidative stress-elicited aging are two mechanisms of aging that are likely intertwined, leading to neurodegenerative damages. It is a commonly accepted that neurodegenerative diseases are the consequences of overproduction of oxidative stress or a result of compromised antioxidative mechanisms regardless of their aetiology. In aged brain, microglia increase in number and switch to a more pro-inflammatory state, providing a basis for greater inflammatory responses to inflammogens. Unfortunately, these unfavorable changes are often coupled with compromised capacity to remove oxidative products, allowing mutual perpetuation of inflammation and oxidative damage. This review highlights roles of microglia-mediated neuroinflammation and oxidative stress and association of these two. The possible novel therapeutic approaches are discussed in the context of focusing only on those possessing anti-inflammatory or antioxidative properties.     

Blood-brain barrier P-glycoprotein function in neurodegenerative disease

Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.