黄芩对实验性帕金森模型大鼠的保护作用

目的:研究黄芩对鱼藤酮所致帕金森(PD)模型大鼠的保护作用。方法:Wistar大鼠每日颈、背部皮下注射鱼藤酮葵花油乳化液制备PD大鼠模型;阳性组及不同剂量药物组在每日注射鱼藤酮之前1小时灌胃给药。ELISA法检测大鼠脑硫氧还蛋白(Trx);荧光探针法检测纹状体活性氧(ROS);分光光度法检测纹状体谷胱甘肽(GSH)、黑质丙二醛(MDA)含量。结果:造模后模型组大鼠出现一定程度的行为学变化,模型组Trx含量明显低于空白组、阳性组和低剂量组,药物可以一定程度上抑制氧化应激反应。结论:黄芩可以提高帕金森大鼠脑内Trx的表达,对鱼藤酮所致帕金森模型大鼠具有保护作用,这种作用可能与Trx相关。     

脱氢异雄酮缓解急性肺损伤及其机制研究

目的探讨脱氢异雄酮(DHEA)对脂多糖(LPS)诱导的急性肺损伤(ALI)小鼠模型中气道上皮细胞(AECs)中G6PD活性、NOX2表达、活性氧(ROS)产生和酶抗氧化剂的影响。方法选取32只SPF级Balb/c小鼠,随机分为4组:对照组、LPS组、DHEA+LPS处理组、DHEA对照组。应用LPS诱导小鼠ALI模型。给药后进行支气管肺泡灌洗液(BALF)中的中性粒细胞计数、蛋白总浓度检测和肺组织髓过氧化物酶(MPO)活性检测。分析各组小鼠肺组织中谷胱甘肽还原酶活性、G6PD活性、GR活性和ROS。实时PCR分析SOD1、SOD2、GPx1基因表达,流式细胞仪检测SOD1和硝基酪氨酸表达。结果 ALI导致AECs中G6PD活性增加,同时伴随着NOX2、ROS、SOD1和硝基酪氨酸的升高,G6PD抑制剂DHEA可有效改善LPS诱导的气道炎症,降低支气管肺泡灌洗液蛋白质浓度及NOX2衍生的ROS和氧化应激。结论 G6PD的激活与ALI期间氧化炎症的增强有关。因此,在ALI期间抑制G6PD可能是一种有益的策略,以限制氧化损伤和改善气道炎症。     

褪黑素抗氧化保护作用机制及应用的研究进展

褪黑素(MT)除具有调节睡眠、生殖及昼夜节律等生理功能外，还具有抗氧化活性，是一种高效自由基清除剂。从抗氧化的化学机制方面看，MT为高选择性电子供体，不易发生氧化还原循环反应，也无促氧化副作用。从抗氧化的生物学机制方面看，MT通过保护生物大分子，抑制细胞凋亡和诱导抗氧化防御酶发挥抗氧化效应。体内外动物实验表明，MT对神经性疾病、环境化合物的靶器官毒性、自发性和诱发性肿瘤、糖尿病和胚胎发育异常等自由基损伤性疾病都有不同程度的保护作用。     

叠氮钠造成脑线粒体损伤模型的研究现状

现已证明 ,线粒体缺陷与阿尔茨海默病 (AD)的发生密切相关 ,其中AD患者细胞色素C氧化酶 (COX)活性的降低明显且特异。叠氮钠 (NaN3 ) ,一种特异性COX抑制剂 ,可以损伤线粒体活性 ,建立具有部分类似AD病理改变的动物和细胞模型。它可以导致动物学习记忆功能障碍 ,其可能的机制包括细胞骨架结构破坏 ,Aβ沉积 ,氧化损伤 ,离子内稳态破坏 ,细胞膜损伤以及神经递质异常。NaN3 造成的脑线粒体损伤模型为AD机理和治疗药物的研究提供了新的途径。     

丙泊酚对布比卡因诱导的PC12细胞毒性和硫氧还蛋白系统的影响

目的：探讨丙泊酚对布比卡因诱导的PC12细胞毒性的保护作用及内源性硫氧还蛋白（Trx）系统在其中的作用。方法：培养的PC12细胞分成四组，正常对照组、丙泊酚组、布比卡因组、丙泊酚＋布比卡因（PB）组，每组6孔。培养6h和24h后，用MTT比色微量分析细胞存活率，测定上清液乳酸脱氢酶（LDH）活性和细胞内硫氧还蛋白还原酶（TrxR）、活性氧（ROS）活性，RT-PCR检测Trx-1 mRNA和TrxR-1 mRNA表达。结果：与正常PC12细胞相比，布比卡因可显著降低细胞存活率（P〈0．01）和细胞内TrxR活性（P〈0．05），增加上清液中LDH活性和细胞内ROS活性（P〈0．05，P〈0．01），明显降低Trx mRAN和Trx mRAN表达（P〈0．05）；丙泊酚对正常PC12细胞无明显影响；与布比卡因组相比，PB组细胞存活率（P〈0．01）和细胞内Trx活性（P〈0．05）明显增加，上清液中LDH活性和细胞内ROS活性显著降低（P〈0．05，P〈0．01），Trx mRAN和Trx mRAN表达明显增加（P〈0．05）。结论：布比卡因对PC12细胞具有毒性作用可能与降低细胞内TrxR活性、增加ROS活性有关，丙泊酚通过保护细胞内Trx系统的活性及清除ROS来减轻布比卡因诱导的PC12细胞毒性。     

阿尔茨海默病发生机制研究的新方向--胆固醇代谢

载脂蛋白E(ApoE)基因作为阿尔茨海默病(AD)发生的基因危险因素,揭示了胆固醇代谢与AD密切关系.作为AD显著病理标志的β淀粉样肽(Aβ)的异常产生和沉积受胆固醇的调节.这种调节具有双向性.在AD的细胞和大多数动物模型中均证实胆固醇升高可增加Aβ的生成,并且胆固醇在神经元的分布影响Aβ的产生和代谢.而Aβ可改变胆固醇在神经元的动力学分布从而导致tau蛋白磷酸化.脑内胆固醇的氧化代谢产物24-羟化胆固醇的堆积也可能导致神经元的损伤.他汀类等胆固醇代谢的调节药物有望成为AD有效的治疗手段.     

穿心莲内酯衍生物体外抗肿瘤作用及构效关系研究

目的:研究穿心莲内酯(AD)及其3,19-缩醛(酮)衍生物(3~15)、14-脱氧-11,12-二脱氢穿心莲内酯(ADD)C-15取代(16~28)及其复合8,17环氧化(31~34)等衍生物的体外抗肿瘤活性,用于指导抗肿瘤候选药物的合成。方法:以人食管癌Ec9706、人肺腺癌A549为模型,采用MTT法评价衍生物的活性,并进行初步的构效关系研究。结果:化合物3~15对2株肿瘤细胞的细胞毒活性较AD显著提高,其中化合物6对Ec9706的IC50为4.7μmol.L-1,而AD的IC50为81.7μmol.L-1。ADD的肿瘤细胞毒活性低于AD。不同的C-15取代基导致化合物16~28和31~34活性差异很大。AD的羟基乙酰化产物(35~37)活性比AD高,ADD的羟基乙酰化产物(38,39)活性比ADD低。结论:对AD的C-3,C-14,C-19羟基进行修饰、ADDC-15取代或C-15取代复合C-8,17双键环氧化可获得一系列体外抗肿瘤活性显著提高的衍生物。     

槲皮素对葡萄糖-6-磷酸脱氢酶缺乏者红细胞的体外氧化作用

目的探讨槲皮素对葡萄糖-6-磷酸脱氢酶(G6PD)缺乏者红细胞氧化还原状态的影响。方法分别在体外将低、中、高浓度的槲皮素与G6PD缺乏者及正常者的40%红细胞悬液和全血进行孵育,然后测定红细胞还原性谷胱甘肽(GSH))及高铁血红蛋白(MetHb)水平的变化。结果槲皮素具有较强氧化作用,能明显降低G6PD缺乏者红细胞GSH水平,升高MetHb,且这种氧化作用呈一定浓度依赖性,在中、高浓度表现明显。结论槲皮素对G6PD缺乏者红细胞具有氧化作用,G6PD缺乏者应慎用含槲皮素成分的食物、中草药及制剂。     

黄酮类化合物对葡萄糖-6-磷酸脱氢酶缺乏者红细胞的体外氧化作用

目的:探讨黄酮类化合物对葡萄糖-6-磷酸脱氢酶(G6PD)缺乏者红细胞氧化还原状态的影响。方法:将低、中、高浓度的槲皮素、黄芩素、芹菜素、漆黄素、木犀草素、柚皮素、桑黄素、山奈酚、葛根素和芦丁分别与G6PD缺乏者及正常者红细胞在40%红细胞悬液和全血中进行体外孵育,测定红细胞还原性谷胱甘肽(GSH)和高铁血红蛋白(MetHb)的水平。结果:槲皮素、黄芩素、芹菜素、漆黄素、木犀草素、柚皮素、桑黄素、山奈酚具有较强的氧化作用,能明显降低G6PD缺乏者红细胞GSH水平,升高MetHb水平。葛根素仅降低G6PD缺乏者红细胞GSH水平,具有较弱的氧化作用。芦丁对G6PD缺乏者红细胞GSH和MetHb均无影响。较高浓度的槲皮素、芹菜素、桑黄素亦能使G6PD正常者MetHb水平升高。黄酮类化合物的氧化作用呈一定浓度依赖性,在中、高浓度时表现明显。结论:部分黄酮类化合物对G6PD缺乏者红细胞具有氧化作用,建议G6PD缺乏者慎用富含氧化性黄酮类化合物的中草药及其制剂。     

酸度对木犀草素Cu(Ⅱ)修饰碳糊电极的电化学性质的影响

目的：研究了木犀草素Cu(Ⅱ)修饰碳糊电极在B-R缓冲溶液中的电化学行为。方法：用循环伏安法对木犀草素Cu(Ⅱ)修饰碳糊电极的氧化还原性质进行研究。结果：发现木犀草素Cu(Ⅱ)有一对可逆的氧化还原峰和一个不可逆的还原峰,且峰位随酸度增加向正电位方向移动。结论：木犀草素Cu(Ⅱ)具有良好的电化学活性,同时酸度对电极电位有较大影响。     

Levodopa activates apoptosis signaling kinase 1 (ASK1) and promotes apoptosis in a neuronal model: implications for the treatment of Parkinson's disease

Oxidative stress is implicated in the etiology of Parkinson's disease (PD), the second most common neurodegenerative disease. PD is treated with chronic administration of l-3,4-dihydroxyphenylalanine (levodopa, L-DOPA), and typically, increasing doses are used during progression of the disease. Paradoxically, L-DOPA is a pro-oxidant and induces cell death in cellular models of PD through disruption of sulfhydryl homeostasis involving loss of the thiol-disulfide oxidoreductase functions of the glutaredoxin (Grx1) and thioredoxin (Trx1) enzyme systems [Sabens, E. A., Distler, A. M., and Mieyal, J. J. (2010) Biochemistry 49 (12), 2715-2724]. Considering this loss of both Grx1 and Trx1 activities upon L-DOPA treatment, we sought to elucidate the mechanism(s) of L-DOPA-induced apoptosis. In other contexts, both the NFκB (nuclear factor κB) pathway and the ASK1 (apoptosis signaling kinase 1) pathway have been shown to be regulated by both Grx1 and Trx1, and both pathways have been implicated in cell death signaling in model systems of PD. Moreover, mixed lineage kinase (MLK) has been considered as a potential therapeutic target for PD. Using SHSY5Y cells as model dopaminergic neurons, we found that NFκB activity was not altered by L-DOPA treatment, and the selective MLK inhibitor (CEP-1347) did not protect the cells from L-DOPA. In contrast, ASK1 was activated with L-DOPA treatment as indicated by phosphorylation of its downstream mitogen-activated protein kinases (MAPK), p38 and JNK. Chemical inhibition of either p38 or JNK provided protection from L-DOPA-induced apoptosis. Moreover, direct knockdown of ASK1 protected from L-DOPA-induced neuronal cell death. These results identify ASK1 as the main pro-apoptotic pathway activated in response to L-DOPA treatment, implicating it as a potential target for adjunct therapy in PD.     

Therapeutic induction of autophagy to modulate neurodegenerative disease progression

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington''s disease (HD), Parkinson''s disease (PD) and amyotropic lateral sclerosis.     

Potential of Medicinal Plants as Neuroprotective and Therapeutic Properties Against Amyloid-β-Related Toxicity,and Glutamate-Induced Excitotoxicity in Human Neural Cells

Alzheimer’s disease (AD) and Parkinson''s disease (PD) are notorious neurodegenerative diseases amongst the general population. Being age-associated diseases, the prevalence of AD and PD is forecasted to rapidly escalate with the progressive aging population of the world. These diseases are complex and multifactorial. Among different events, amyloid β peptide (Aβ) induced toxicity is a well‐established pathway of neuronal cell death, which plays a vital function in AD. Glutamate, the major excitatory transmitter, acts as a neurotoxin when present in excess at the synapses; this latter mechanism is termed excitotoxicity. It is hypothesised that glutamate-induced excitotoxicity contributes to the pathogenesis of AD and PD. No cure for AD and PD is currently available and the currently approved drugs available to treat these diseases have limited effectiveness and pose adverse effects. Indeed, plants have been a major source for the discovery of novel pharmacologically active compounds for distinct pathological conditions. Diverse plant species employed for brain-related disorders in traditional medicine are being explored to determine the scientific rationale behind their uses. Herein, we present a comprehensive review of plants and their constituents that have shown promise in reversing the (i) amyloid-β -related toxicity in AD models and (ii) glutamate-induced excitotoxicity in AD and PD models. This review summarizes information regarding the phytochemistry, biological and cellular activities, and clinical trials of several plant species in view to provide adequate scientific baseline information that could be used in the drug development process, thereby providing effective leads for AD and PD.     

The mitochondrial dynamics of Alzheimer's disease and Parkinson's disease offer important opportunities for therapeutic intervention

Mitochondrial dynamics play a crucial role in the pathobiology underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Although a complete scientific understanding of these devastating conditions has yet to be realized, alterations in mitochondrial fission and fusion, and in the protein complexes that orchestrate mitochondrial fission and fusion, have been well established in AD- and PD-related neurodegeneration. Whether fission/fusion disruption in the brain is a causal agent in neuronal demise or a product of some other upstream disturbance is still a matter of debate; however, in both AD and PD, the potential for successful therapeutic amelioration of degeneration via mitochondrial protection is high. We here discuss the role of mitochondrial dynamics in AD and PD and assess the need for their therapeutic exploitation.     

Determination of glutathione S-transferase mu and theta polymorphisms in neurological disease

1. Correlations between deletions in two glutathione S-transferase (GST) genes, GSTM1 and GSTT1 and susceptibility to Alzheimer's disease (AD), motor neuron disease (MND) and Parkinson's disease (PD) have been investigated by PCR, using primers specific for both genes. 2. It was found that males with a deletion of the GSTM1 gene were more susceptible to PD and males with a deletion of the GSTT1 gene more susceptible to MND and PD, possibly implying that environmental factors which specifically target men may be involved. Furthermore, subjects with a deletion of the GSTT1 gene were more susceptible to AD.     

氧化应激和阿尔茨海默病

阿尔茨海默病(Alzheimer’sdisease,AD)是一种以进行性认知功能障碍和记忆力损害为主的中枢神经系统退行性疾病,该病是由多种因素共同作用引起的,其中自由基损伤在发病机理中起重要作用。据报道,抗氧化剂在延缓AD病的进程和改善认知能力上有一定疗效。本文就氧化应激自由基损伤与AD的关系以及抗氧化剂研究现状作一综述。     

Curcumin and neurodegenerative diseases: a perspective

Introduction: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD).

Areas covered: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed.

Expert opinion: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.     

Inhibition of Membrane-Bound Aminopeptidase P

The two most common neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD). The symptoms are caused by the initially selective degeneration of neuronal subpopulations involved in memory (AD) or movement control (PD). The cause of both diseases is unknown, but ageing is an inevitable risk factor. The identification of disease-associated genes was a breakthrough for the understanding of molecular mechanisms of neurodegeneration and has provided the basis for the establishment of cell culture and animal model systems, instrumental for target validation and drug screening. Familial AD is caused by mutations in the β-amyloid precursor protein (βAPP) and in the gene products responsible for its proteolytic processing, namely the presenilins. Transgenic mice expressing these mutant genes develop characteristic AD plaques in an age-dependent manner. A reduction of plaque burden and amelioration of cognitive decline in these animals was recently achieved by vaccination with amyloid β-protein fibrils. The other hallmark lesion of AD, the neurofibrillary tangle, has been modelled recently in transgenic mice expressing mutant tau protein linked to frontotemporal dementia. PD is characterised by intraneuronal cytoplasmic deposits (Lewy bodies) of the PD-associated gene product α-synuclein. Transgenic expression of α-synuclein recreated hallmark features of PD in mice and fruit flies, establishing α-synuclein as PD-causing drug target. Moreover, environmental risk factors such as the pesticide rotenone have been used successfully to generate rodent models of PD. Lesion models of PD are being exploited for the development of experimental gene therapy and transplantation approaches.     

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.