补肾填精方防治阿尔茨海默病模型大鼠学习记忆损害的分子机制

目的探讨补肾填精方防治铝致阿尔茨海默病(AD)的分子机制。方法用长期腹腔注射AlCl3复制大鼠动物模型,用RT-PCR检测端脑皮质beta-淀粉样前体蛋白mRNA异构体-APP695mRNA水平,用Y电迷宫仪检测大鼠的学习记忆能力。结果模型组大鼠端脑皮质APP695mRNA的表达水平明显升高(P<0.05),学习记忆能力明显降低(P<0.05)。中药干预后,端脑皮质APP695mRNA表达较模型组明显降低(P<0.01),学习记忆能力明显提高(P<0.05)。结论端脑皮质APP695mRNA表达水平升高与学习记忆能力减低明显相关,通过抑制端脑皮质APP695mRNA的过量表达是补肾填精方防治AD模型大鼠学习记忆能力损害的机制之一。     

β淀粉样蛋白及代谢酶类在阿尔茨海默病和糖尿病模型小鼠脑内的表达

目的观察阿尔茨海默病(AD)和糖尿病模型小鼠脑内β淀粉样蛋白(Aβ)及代谢相关酶类的表达情况,以便从分子水平找到糖尿病并发AD的实验室依据。方法 5月龄双转基因痴呆症模型小鼠(APP/PS1双转基因小鼠)、ob/ob T2DM肥胖模型小鼠和野生型C57BL/6J小鼠为对照,分别用免疫组化染色、ELISA和Western blot检测脑内老年斑(SP)、Aβ含量及Aβ代谢酶类的表达情况。结果 APP/PS1小鼠大脑皮质及海马均可见一定数量的SP;ob/ob小鼠大脑皮质内偶可见SP,而对照组未见SP。与对照小鼠相比,APP/PS1与ob/ob小鼠脑内Aβ40、Aβ42的含量明显升高(P0.05);但APP/PS1小鼠脑内Aβ水平显著高于ob/ob小鼠(P0.05)。APP在APP/PS1小鼠脑内的表达显著高于其他两组小鼠;在ob/ob小鼠脑内的表达要强于对照小鼠(P0.05)。Aβ生成的关键酶BACE1在APP/PS1与ob/ob小鼠脑内的表达显著高于对照小鼠(P0.05),但其在APP/PS1小鼠脑内的表达要强于ob/ob小鼠(P0.05)。Aβ降解的关键酶IDE在APP/PS1与ob/ob小鼠脑内的表达显著低于对照小鼠(P0.05),且在ob/ob小鼠脑内表达最低。结论 Aβ生成与降解的异常以及其异常聚集沉积不仅发生在早期AD脑内,同时也发生在T2DM脑内,提示Aβ过表达可能是促进2型糖尿病并发AD的重要原因之一。     

Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid

The components of the herb Magnolia officinalis have exhibited antioxidant and neuroprotective activities. In this study, we investigated effects of ethanol extract of M.officinalis and its major component 4-O-methylhonokiol on memory dysfunction and neuronal cell damages caused by Aβ. Oral pretreatment of ethanol extract of M. officinalis (2.5, 5 and 10 mg/kg) and 4-O-methylhonokiol (1 mg/kg) into drinking water for 5 weeks suppressed the intraventricular treatment of Aβ_1-42 (0.5 μg/mouse, i.c.v.)-induced memory impairments. In addition, 4-O-methylhonokiol prevented the Aβ_1-42-induced apoptotic cell death as well as β-secretase expression. 4-O-methylhonokiol also inhibited H₂O₂ and Aβ_1-42-induced neurotoxicity in cultured neurons as well as PC12 cells by prevention of the reactive oxygen species generation. 4-O-methylhonokiol also directly inhibited β-secretase activity and Aβ fibrilization in vitro. Thus, ethanol extract of M. officinalis may be useful for prevention of the development or progression of AD, and 4-O-methylhonokiol may be a major active component.     

Indole-2-carboxamide derivatives: a patent evaluation of WO2015036412A1

Introduction: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson`s and Alzheimer`s Disease to various brain injuries.

Areas covered: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature.

Expert opinion: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously.     

老年痴呆模型中人参皂苷Rg1预处理对大鼠脑片中突触素表达的影响

【摘要】 目的 通过冈田酸（OA）诱导大鼠脑片老年痴呆模型,观察用人参皂苷Rg1干预后对大鼠脑片中突触素(SYN)表达的影响,以探究中药人参皂苷Rg1抗老年痴呆的作用机制。方法 将冈田酸作用于SD大鼠脑片,构建老年痴呆病理模型。随机分为空白组、模型组和人参皂苷Rg1低、中、高药物干预组,每组10张脑片。脑片置人工脑脊液中培养,干预结束后固定切片处理。采用免疫组织化学染色、图像分析技术等方法,检测皮层和海马SYN的表达水平。结果 与空白组比较,模型组皮层和海马内SYN的蛋白表达量明显减少（P＜0.05）,人参皂苷Rg1各浓度组SYN的蛋白表达量增加（P＜0.05）,并呈浓度依赖性。结论 人参皂苷Rg1可能通过影响突触素的活性表达,发挥抗老年痴呆神经退行性变的作用,减缓大脑的老化过程,从而起到保护大脑的作用。     

APP/PS1转基因AD鼠海马CA1区神经元突触超微结构

目的:探讨携带5个家族性基因突变的APP/PS1转基因阿尔茨海默病(AD)(5×FAD)模型小鼠海马CA1区神经元突触超微结构改变。方法:应用透射电镜观察和形态计量学分析5×FAD转基因AD鼠海马CA1区GrayⅠ型突触界面结构参数,包括突触间隙长度、突触间隙面积、突触后致密物浓度和突触界面曲率的变化。结果:5×FAD转基因AD鼠海马CA1区神经元突触活性区长度显著小于对照组,差异有统计学意义;突触后致密物厚度、突触界面曲率及宽度与对照组差异无统计学意义。结论:5个家族性突变基因导致小鼠海马CA1区神经元突触可塑性的改变,这可能是该突变基因导致的发病机制之一。     

神经生长因子缓释微球植入后阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元的变化

背景：已有研究表明,神经营养因子对中枢和周围神经损伤后的存活修复有促进作用。然而,神经生长因子是大分子蛋白类物质,生物半衰期很短,很难透过血脑屏障,寻找有效的神经营养因子投递系统至关重要。 目的：观察了神经生长因子微球对阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元的保护作用。 设计、时间及地点：随机对照动物实验,于2005-11/2006-07在广州医学院神经生物学实验室完成。 材料：采用双乳化技术制备神经生长因子缓释微球。28只SD大鼠,随机分为3组：正常对照组8只,模型对照组8只,神经生长因子缓释微球植入组12只。 方法：模型对照组和神经生长因子缓释微球植入组左侧穹隆海马伞切断制备阿尔茨海默病模型,正常对照组不做任何处理。神经生长因子缓释微球植入组切断后即刻行基底前脑注射神经生长因子缓释微球。正常对照组和模型对照组注射等量生理盐水。 主要观察指标：注射4周后,利用免疫组化法观察各组大鼠基底前脑神经生长因子受体阳性神经元变化。 结果：28只大鼠均进入结果分析。模型对照组损伤侧的内侧隔核和斜角带核的神经生长因子受体阳性神经元大量减少,分别减少59.7%和54.4%;神经生长因子缓释微球植入组损伤侧的内侧隔核和斜角带核细胞数分别减少17.9%和19.8%,明显高于模型对照组损伤侧的神经生长因子受体阳性神经元存活数（P < 0.05）。 结论：神经生长因子缓释微球植入对阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元有明显的保护作用。     

p38 MAPK inhibitors: a patent review (2012 – 2013)

Introduction: The p38 MAPK is a ubiquitous target in the research-based pharmaceutical industry. It plays a decisive role in the regulation of the production of proinflammatory cytokines. Since novel biological therapies have revolutionized the treatment of chronic inflammatory diseases, an intensive global search is underway for small molecules for the same application.

Areas covered: Herein, the patents and the corresponding publications of international companies, which focus on the development and identification of a new generation of small-molecule p38 inhibitors, are summarized.

Expert opinion: The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.     

Psychosocial interventions in Alzheimer's disease and amnestic mild cognitive impairment: evidence for gender bias in clinical trials

Background: Alzheimer's disease (AD) affects twice as many women as men. Gender differences in symptom profile, living conditions, coping style and response might affect the outcome of psychosocial interventions (PSIs).

Objectives: Our aim was to review gender differences in the available high-quality phase III trials on PSI in AD and amnestic mild cognitive impairment (aMCI) by considering the gender ratio in the investigated samples.

Design: Randomized controlled trials published in 2000–2012 were stepwise analyzed by statistically testing the representativeness of the gender ratio and examining reported gender differences.

Results: Forty-five studies (62% of 73 studies) reported gender ratios for each subsample and were included. In these studies, females were underrepresented in the control groups. In the 14 studies (19%) reporting analyses of gender differences, women were underrepresented in both intervention and control groups. However, in the six studies (8%) reporting significant gender differences in outcome, gender distribution was in accordance with prevalence rates.

Conclusion: Current evidence is insufficient for reliable conclusions on gender differences in PSI outcome in AD and aMCI, as 81% of the available clinical trials either not reported the gender ratio of their samples, or underrepresent females. Further research is needed addressing gender differences, and clinical trials should routinely control for gender bias.