Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid

Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.     

β-淀粉样蛋白对大鼠学习记忆、病理及tau蛋白磷酸化的影响

目的研究大鼠海马区内注射β-淀粉样蛋白（Aβ）的神经毒性,建立阿尔茨海默病（AD）动物模型,探讨Aβ毒性机制。方法选取雌性成年SD大鼠24只,随机分为止常对照组、生理盐水组、AD组,每组8只。Morris水迷宫检测大鼠学习记忆功能,HE染色及B ielschowsk i染色法观察海马神经元形态,免疫组化法观察tau蛋白异常磷酸化变化。结果与正常对照组大鼠相比,AD组大鼠水迷富测试结果明显减退（P〈0.01）;海马CA1区神经元纤维形态紊乱,tau蛋白磷酸化阳性细胞数明显增多（P〈0.01）。结论大鼠海马内注射凝集态Aβ可产生神经毒性作用,能较好地模拟AD行为和病理表现,其神经毒性可能是通过tau蛋白的异常磷酸化起作用。     

Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors

Galantamine is currently used to treat Alzheimer's disease patients; it behaves as a mild blocker of acetylcholinesterase (AChE) and has an allosteric modulating action on nicotinic acetylcholine receptors (nAChRs). In this study, we observed that galantamine prevented cell death induced by the peptide beta-amyloid(1-40) and thapsigargin in the human neuroblastoma cell line SH-SY5Y, as well as in bovine chromaffin cells. The protective effect of galantamine was concentration-dependent in both cell types; maximum protection was produced at 300 nM. The antiapoptotic effect of galantamine at 300 nM, against beta-amyloid(1-40) or thapsigargin-induced toxicity, was reversed by alpha-bungarotoxin. At neuroprotective concentrations, galantamine caused a mild and sustained elevation of the cytosolic concentration of calcium, [Ca2+]c, measured in single cells loaded with Fura-2. Incubation of the cells for 48 h with 300 nM galantamine doubled the density of alpha7 nicotinic receptors and tripled the expression of the antiapoptotic protein Bcl-2. These results strongly suggest that galantamine can prevent apoptotic cell death by inducing neuroprotection through a mechanism related to that described for nicotine, i.e. activation of nAChRs and upregulation of Bcl-2. These findings might explain the long-term beneficial effects of galantamine in patients suffering of Alzheimer's disease.     

Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade

Administration of drugs activating cannabinoid CB(1) receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of beta-amyloid or beta-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB(1) receptors in amnesia induced by beta-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of beta-amyloid fragments, beta-amyloid peptide-(25-35) (4, 8 or 16 nmol/mouse) or beta-amyloid peptide-(1-42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two beta-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB(1) receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that beta-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB(1) receptors in the brain.     

Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro

The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid beta-peptides (A beta) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of beta-amyloid fibrils (fA beta) at pH 7.5 at 37 degrees C in vitro. All examined NSAIDs dose-dependently inhibited formation of fA beta from fresh A beta(1-40) and A beta(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fA betas. The overall activity of the molecules examined was in the following order: ibuprofen approximately sulindac sulfide >or= meclofenamic acid sodium salt>aspirin approximately ketoprofen >or= flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. Although the mechanisms by which these NSAIDs inhibit fA beta formation from A beta, and destabilize preformed fA beta in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.     

alpha7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in beta-amyloid infused rats

Continuous intracerebroventricular infusion of beta-amyloid peptide 1-40 (Abeta(1-40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. Beta-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from Abeta-infused brain. Throughout this study, an effort was made to address whether the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which is believed to be a primary target of Abeta [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Abeta (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155-1161.], is responsible for the deficits in synaptic plasticity observed in the Abeta-infused rats. First, we found that Abeta-infusion markedly depressed the response of alpha7nAChR to a selective alpha7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of alpha7nAChR with either methyllycaconitine (MLA) or alpha-bungarotoxin (alpha-BTX) in control rats inhibited LTP induction, suggesting that the activation of alpha7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Abeta-infused rats with 10 microM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Abeta-impaired LTP and PPF arise as a consequence of dysfunctional alpha7nAChR, and that alpha7nAChR may be an important target to help ameliorate AD patient cognitive deficits.     

氯化锂抑制β-淀粉样蛋白诱导细胞Tau蛋白磷酸化

目的探讨GSK-3β抑制剂氯化锂(LiCl)在β-淀粉样蛋白25～35片断(Aβ25-35)诱导的细胞Tau蛋白磷酸化中的作用及机制。方法MTT法观察不同浓度的LiCl(1、5、10、20mmol.L-1)单独作用24h,对SH-SY5Y细胞存活率的影响;20μmol.L-1的凝聚态Aβ25-35作用于SH-SY5Y细胞不同时间点,蛋白免疫印迹法研究Tau蛋白磷酸化位点(Ser199、Ser396及Tau1)水平的变化;LiCl(20mmol.L-1)预处理细胞1h后,观察Aβ的作用有无变化及可能的作用机制。结果不同浓度的LiCl作用24h后,MTT法示细胞存活率无明显变化(P>0.05);20μmol.L-1Aβ25-35作用不同时间点后,Tau蛋白在Ser396、Ser199位点的磷酸化水平在3h逐渐增加,6h达到最高峰,12h后又逐渐下降,在这3个时间点的增加量均具有统计学意义(P<0.05),而对非磷酸化Tau1没有影响(P>0.05);LiCl预处理可抑制Aβ25-35的作用(P<0.05),并可诱导失活形式的GSK-3β在Ser9位点的磷酸化(p-GSK-3βSer9)表达增高。结论GSK-3β参与了Aβ25-35诱导细胞Tau蛋白磷酸化的作用,LiCl可通过诱导失活形式的p-GSK-3βSer9表达增高而抑制GSK-3β的活性,进而抑制Aβ诱导的细胞Tau蛋白磷酸化。该实验为研究AD的发病机制及探索有效治疗药物提供了重要的理论基础。     

甲硫哒嗪损伤大鼠学习记忆伴随脑β-淀粉样蛋白的升高

目的观察甲硫哒嗪损伤大鼠学习记忆是否伴随脑内β-淀粉样蛋白(β-amyloid protein,Aβ)水平的升高,探讨甲硫哒嗪引起认知功能受损的机制。方法20只大鼠随机分为对照组和甲硫哒嗪组,连续2wk分别腹腔注射生理盐水和治疗剂量的甲硫哒嗪(10mg·kg-1)。用Morris水迷宫测定大鼠学习记忆能力,用放射免疫分析法测脑组织Aβ含量,用免疫组织化学染色检测β-淀粉样前体蛋白(β-amyloid precursor protein,APP)表达,用RT-PCR方法测定脑中3种APP、α及β-分泌酶mRNA表达。结果甲硫哒嗪组大鼠学习记忆能力下降,脑组织Aβ含量升高(P<0.05),是对照组的1.3倍;脑皮质和海马区APP蛋白表达增高(P<0.05);除APP695、α-分泌酶mRNA表达变化无统计学意义外,脑组织APP751和APP770 mRNA表达升高(P<0.05),相对表达量之和是对照组的2.5倍;β-分泌酶mRNA表达升高(P<0.05),是对照组的2.6倍。结论脑内Aβ水平的增加,可能是甲硫哒嗪引起认知功能损害的原因之一。     

Effect of 17-beta-estradiol and ginsenoside Rg1 on reactive microglia induced by beta-amyloid peptides

The reactive microglias induced by 25 μmol of β-amyloid peptides (Aβ25-35) and/or IFN-γ can initiate the microglial respiratory burst and release NO, respectively. Oxidative stress and inflammatory function have been implicated in Alzheimer's disease (AD). We showed that 10 μmol 17-β-estradiol (E₂) and 1-10 μmol ginsenoside Rg₁ (Rg₁) could prevent the toxicity of Aβ25-35 and/or IFN-γ to microglias, inhibit the microglial respiratory burst activity and decrease the accumulation of NO. These results demonstrated the protectional effect of E₂ or Rg₁ on neuron from damaging by reactive microglias in AD.     

低分子肝素联合氯沙坦治疗糖尿病肾病临床观察

目的观察低分子肝素联合氯沙坦对糖尿病肾病的疗效。方法60例糖尿病肾病患者,分为对照组和治疗组,在糖尿病治疗方案的基础上,比较氯沙坦与低分子肝素钙联合氯沙坦对24h尿蛋白、BUN、Scr的影响。结果低分子肝素联合氯沙坦可使24h尿蛋白显著下降,尿β2MG及血尿酸明显改善(P<0.05),无一例出现瘀斑。结论低分子肝素联合氯沙坦对糖尿病肾病有明显疗效,并且具有出血危险性小的优点。     

低分子肝素与普通肝素辅助治疗老年重症肺炎的效果对比分析

目的 比较分析低分子肝素与普通肝素辅助治疗老年重症肺炎的效果.方法 选取本院2013年1月至2015年1月收治的老年重症肺炎患者100例作为观察对象,根据患者具体用药的不同将其分为低分子肝素组(观察组)和普通肝素组(对照组),分析比较治疗后两组临床效果、相关检测指标等.结果 观察组治疗总有效率89.29％,明显高于对照组的79.55％,差异具有统计学意义(P＜0.05).治疗后,观察组体温[(36.46±0.67)℃]、WBC[(8.67±3.88)×109/L]、RR[(16.45±2.73)次/min]、HR[(76.79±4.95)次/min]、Sa02[(96.68±4.49)％]、Pa0JFi02[(222.47±35.89)]mmHg(1mmHg=0.133 kPa)各项检测指标均好于对照组.结论 老年重症肺炎患者在常规治疗基础上加用低分子肝素在改善肺部氧合、抗凝等方面具有积极意义.     

肝素类药物防治阿尔采末病的研究进展

本文分析了阿尔采末病(AD)的病理机制,对肝素类药物神经保护机制的进展进行了综述。阐明了肝素类药物可通过调节IP3受体介导的细胞内钙释放,影响淀粉样蛋白(Aβ)沉积及其毒性、调节tau蛋白的磷酸化状态,保护胆碱能神经元等发挥神经保护作用,从而延缓AD的发生与发展。     

低分子肝素和普通肝素治疗急性肺栓塞疗效研究

目的探究低分子肝素与普通的肝素治疗急性肺栓塞的临床疗效。方法将我院2010年2月至2012年2月之间收录的68例急性肺栓塞患者随机的分为两组,A组34例患者给予低分子肝素进行治疗,而B组34例患者给予普通肝素进行治疗,观察两组治疗的临床效果。结果通过两组的患者治疗效果分析,A组和B组的患者治疗效果和不良反应发生率的比较无明显的差异(P>0.05)。结论低分子肝素与普通的肝素治疗急性肺栓塞的临床效果相似,效果明显,值得临床中应用。     

Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery

Low molecular weight heparins (LMWHs), the anticoagulant drug of choice in many indications, had been suggested as novel drug treatment for a range of diseases. Their superior pharmacokinetic properties compared to unfractionated heparin (UFH), motivated scientists to explore new delivery systems for improved therapeutic outcomes. Micro- and nano-carriers, with the versatile nature and characteristics of materials used for their fabrication, are able to surmount the challenges opposed by their native structures. The present review discusses the recent perspectives on the development of micro- and nano-particulate vectors for the delivery of LMWHs through various routes. Special focus on the application of the suggested systems, their characterization and the achieved improved bioavailability will be given throughout the review.     

低分子量肝素的研究进展

低分子量肝素是一种新型抗凝药,具有抗凝血、抗血栓、抗肿瘤等作用,与普通肝素相比具有皮下注射吸收好、半衰期长、生物利用率高等优点。本文介绍了低分子量肝素的化学结构、作用机制及其应用,并对低分子量肝素的制备方法进行了综述。     

Dehydroevodiamine attenuates tau hyperphosphorylation and spatial memory deficit induced by activation of glycogen synthase kinase-3 in rats

Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD), and glycogen synthase kinase-3 (GSK-3) plays a crucial role in these AD-like changes. We have reported that activation of GSK-3 through ventricular injection of wortmannin and GF-109203X (WT/GFX, 100 microM each) induces tau hyperphosphorylation and memory impairment of rats [Liu, S.J. et al., 2003. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem. 87, 1333-1344]. By using this model, we explored in the present study the effects of dehydroevodiamine (DHED), a quinazoline alkaloid isolated from Evodia rutaecarpa Bentham, on the memory retention, tau phosphorylation and the activity of GSK-3. We found that pre-administration of DHED through vena caudalis for 1 week efficiently improved the WT/GFX-induced spatial memory retention impairment of the rats; it also antagonized tau hyperphosphorylation at multiple AD sites and arrested the overactivation of GSK-3 induced by WT/GFX. Our study gave the first in vivo evidence that DHED could suppress the overactivation of GSK-3 and improve tau hyperphosphorylation and spatial memory deficit of the rats, suggesting that this chemical may be served as a candidate for arresting AD-like pathological and behavioral alterations.     

Faulty regulation of tau phosphorylation by the reelin signal transduction pathway is a potential mechanism of pathogenesis and therapeutic target in Alzheimer''s disease

Hyperphosphorylated tau protein is the basic structural component of the neurofibrillary tangle, a histopathological hallmark of Alzheimer's disease. The formation of hyperphosphorylated tau protein may impair learning and the synaptic plasticity of neurons. Tau is a protein that is associated with and stabilizes microtubules; hyperphosphorylated tau protein is unable to perform this stabilization function. The transduction of reelin, a protein that is crucial to neuronal migration and the formation of synaptic connections in the fetal brain, may have an equally important role in regulating at least some forms of learning and synaptic plasticity in the fully developed mature brain. Reelin transduction is mediated by receptors in the brain that are members of the superfamily of low-density lipoprotein receptors. An important downstream target of reelin signal transduction appears to be inhibition of an enzyme involved in the regulation of tau phosphorylation. The faulty transduction of the reelin signal may be a pathological mechanism leading to hyperphosphorylation of tau protein. Ultimately, inhibition of tau phosphorylation may be an important therapeutic target in Alzheimer's disease and other neuropsychiatric disorders.     

苯并噻唑希夫碱类化合物的合成及其与β-淀粉样蛋白结合性能的研究

阿尔茨海默病(Alzheimer’s disease,AD)是一种神经退行性疾病。随着人口老龄化,发病率逐年增高,不仅严重危害着老年人的健康,而且给家庭、社会带来了巨大的经济和人力负担。在我国1.3亿老年人中,痴呆患者600～700万人,发病率在5%以上,约占世界总病例的1/4,成为世界老年痴呆症第一大国[1]。AD常隐匿起病,逐渐出现记忆力减退、认知     

Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets

Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease. Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some neurotrophins such as transforming-growth-factor β1 (TGF-β1) and brain-derived neurotrophic factor (BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will examine the evidence on the common molecular pathways between depression and Alzheimer's disease and we will discuss these pathways as new pharmacological targets for the treatment of both major depression and Alzheimer's disease.