PPARs与神经退行性疾病

过氧化物酶体增殖剂激活受体(peroxisome prolifera-tion-activated receptors,PPARs)是由配体激活的核转录因子,属于核激素受体(nuclear hormone receptors)超家族。PPARs的激活可能对某些细胞的生长、分化甚至凋亡有重要影响。近年来的研究表明,PPARs具有神经保护作用,可减轻神经退行性疾病所致的脑组织损害,PPARs激动药可能用于阿尔采末病、帕金森病、缺血性脑中风及多发性硬化等神经退行性疾病的治疗。本文对PPARs在中枢神经系统的分布及功能、PPARs介导的信号途径及PPARs对阿尔采末病、帕金森病、缺血性脑中风及多发性硬化等神经退行性疾病的作用做一综述。     

红景天苷的神经保护作用及作用机制研究进展

动物实验结果显示红景天苷对多种原因引起的神经细胞和脑组织损伤均有保护作用,有望用于周围神经损伤以及脑缺血性和神经变性疾病（如脑梗死、老年痴呆、帕金森病、癫痫、抑郁、抽动秽语综合征、肌萎缩性侧索硬化症和糖尿病脑病等）的防治。其神经保护作用机制主要包括3个方面：（1）通过抗氧化作用,抑制NOX2/ROS/MAPKs和REDD1/mTOR/p70S6K信号通路,激活AMPK/SIRT1、RhoA-MAPK和PI3K/Akt信号通路,对抗各种损伤因子引起的氧化应激,抑制炎性细胞因子表达,防止细胞内Ca²⁺超载和半胱天冬酶-3活化,保护神经细胞和干细胞免遭凋亡性损伤;（2）抑制淀粉样前体蛋白β位裂解酶-1的表达和β-分泌酶活性,阻滞内源性伤害因子β-淀粉样肽生成;（3）通过阻滞Notch信号通路,促进BMP信号通路,上调多种神经营养因子表达,诱导间充质干细胞和神经干细胞定向分化成神经元,提高许旺细胞增殖和功能,从而加速神经修复、再生和功能恢复。     

脑缺血耐受机制及雌激素通过此机制介导的神经保护作用

目的对脑缺血耐受的分子机制新近研究及雌激素通过此机制发挥的神经保护作用进行文献综述。方法根据近年来发表的英文文献,归纳并论述脑缺血耐受发生的可能的分子机制,分析药物介导神经保护作用的潜在靶点。结果脑缺血耐受的形成涉及多种不同的信号通路,主要从HSP70、PI3K/Akt信号通路、CREB、炎症因子等方面进行了论述。在缺血预处理模型中,雌激素能够上调HSP70、CREB表达,激活PI3K/Akt信号保护通路,抑制相关炎症因子,加强脑缺血耐受,发挥神经保护作用。结论对脑缺血耐受机制及药物发挥的神经保护作用的研究,为抗脑缺血药物的开发提供新的视角和理论依据。     

脑缺血、葡萄糖/能量代谢障碍与神经退行性疾病

葡萄糖 /能量代谢障碍是引起缺血性脑损伤的主要原因 ,也是神经退行性疾病的综合征之一。由于脑缺血致能量耗竭的过程可分为 3个阶段 ,即缺血开始、完全性能量耗竭和能量恢复阶段。该文通过提供大量科学研究资料 ,如神经化学、细胞学和分子生物学以及病理生理学研究资料来证明葡萄糖 /能量代谢障碍在神经退行性疾病过程中所起的作用 ,对抗脑缺血药的研究进展及其评价作了介绍。     

雏菊叶龙胆酮对局灶性脑缺血损伤的保护作用及机制探讨

目的　研究雏菊叶龙胆酮 (Bellidifolin)对大鼠局灶性脑缺血损伤的保护作用,并探讨其可能的作用机制。方法　利用电凝法制作SD大鼠右侧大脑中动脉阻塞 (MCAO)模型,于MCAO缺血后 4h和 24h进行神经行为学评分, 24评分后断头取脑测量脑梗塞面积,应用HE染色和免疫组化法观察Bellidifolin干预后缺血区病理学改变和ICAM 1、Bcl2蛋白的变化。结果　Bellidifolin能改善MCAO缺血后神经功能障碍并缩小脑梗塞面积;减轻相关脑区神经元损伤程度;显著抑制大鼠局灶性脑缺血损伤ICAM 1表达,上调缺血周边区神经元Bcl 2抗凋亡蛋白的表达。结论　Bellidifoli口服给药对缺血性脑损伤有保护作用,其作用机制可能与抑制ICAM 1表达和促进Bcl 2表达有关。     

荭草苷对脑缺血再灌大鼠的神经保护作用

目的研究荭草苷对脑缺血再灌大鼠的神经保护作用及其作用机制。方法按照体重将大鼠随机分为5组,每组15只:假手术组、模型组、对照组和实验I、II组。除了假手术组以外,其余各组用线栓法建立大鼠局灶性脑中动脉阻断(MCAO)模型。术后0,12 h,对照组和2个实验组均腹腔注射荭草苷溶液2.9 mg·m L^-1,假手术组和模型组给予等剂量0.9%Na Cl。此外,术前0.5,24h,实验I组给予西罗莫司2.24 mg·m L^-1,实验II组给予3-甲基腺嘌呤(3-MA)3.0 mg·m L^-1,其余各组给予相同剂量0.9%Na Cl。脑缺血再灌24 h,进行神经功能评分,以2,3,5-氯化三苯基四氮唑(TTC)法观察大鼠脑梗死体积,以蛋白免疫印迹观察缺血侧脑内自噬相关蛋白Beclin1与微管相关蛋白轻链3(LC3)的表达情况。结果模型组的脑梗死体积为(36.63±2.06)%,高于假手术组(0.67±0.12)%,差异有统计学意义(P<0.01);对照组和实验I、II组的脑梗死体积分别为(14.71±1.63)%,(25.22±1.58)%,(6.45±1.07)%,给药组与模型组比较,差异均有统计学意义(均P<0.05)。自噬相关蛋白Beclin1的相对表达:模型组、假手术组、对照组和实验I、II组分别为3.16±0.17,1.00±0.06,1.67±0.15,2.24±0.13,1.21±0.09;自噬相关蛋白LC3的相对表达,这5组分别为2.98±0.12,1.00±0.05,1.54±0.13,2.24±0.12,1.49±0.17。模型组与假手术组比较,上述指标差异均有统计学意义(均P<0.01);对照组和实验组与模型组比较,给药后差异均有统计学意义(均P<0.05);实验I组与对照组比较,上述指标差异均有统计学意义(均P<0.05)。结论荭草苷对脑缺血再灌大鼠的神经保护作用可能是通过抑制自噬作用来实现的。     

神经元保护剂的研究进展

脑需连续供氧和葡萄糖 ,这是通过调节脑血液循环来完成的。当患有中风和脑缺血 (ｃｅｒｅｂｒａｌｉｓｃｈｅｍｉａ)等疾病时则供应不足。现用的脑血管疾病药物 ,治疗价值有限 ,且疗效不够确切。研究和开发有效药物 ,寻找抗缺血性损害和保护神经元的药物是一项重要的任务。只有了解缺血 缺氧引起神经元损伤的病理变化及药物的作用机制 ,才能研制出更好的新药。脑缺血的易损部位为海马ＣＡ1区的锥体细胞 (兴奋性氨基酸受体密度高 )、纹状体和大脑皮质等处缺血后易发生神经元变性 ,能量代谢紊乱 (供应不足 ) ,ＡＴＰ和葡萄糖含量下降 ,乳酸含…     

黄酮类化合物在防治神经退行性疾病中作用的研究进展

帕金森病、阿尔茨海默病及亨廷顿病等一系列神经退行性疾病的发病因素很多,其中包括神经炎症、内源性抗氧化剂缺失、谷氨酸兴奋性神经毒性损伤以及铁离子代谢异常等。研究表明,黄酮类化合物对神经退行性疾病的临床防治具有一定的疗效。黄酮类化合物可抑制神经炎症、抗氧化应激、抗细胞凋亡、抗谷氨酸神经毒性并调节铁代谢平衡,从而减缓神经细胞损伤并改善学习记忆和脑血管功能。     

Comorbid Mood,Psychosis, and Marijuana Abuse Disorders: A Theoretical Review

ABSTRACT

There is a need to bridge the gap between the fields of addiction psychiatry and general psychiatry to effectively treat co-morbid substance abuse and psychiatric disorders. This alarming epidemic transcends communities and severely impacts healthcare worldwide, yielding poor treatment outcomes and prognoses for afflicted patients. Because substance abuse can exacerbate or trigger psychosis and mood disorders, it is important to keep these issues in the forefront when evaluating patients. To address some of the complications stemming from not enough interactions between various groups of practitioners, this review addresses the neurobehavioral effects of cannabis use and their impact on patients who suffer from psychotic or affective disorders. The hope is that this article will serve as a spring board for further discussions among practitioners who treat these patients. Greater interactions between caretakers are bound to impact the care of our patients in a very positive way.     

NAD+ and NADH in Neuronal Death

Neuronal death is a key pathological event in multiple neurological diseases. Increasing evidence has suggested that NAD⁺ and NADH mediate not only energy metabolism and mitochondrial functions, but also calcium homeostasis, aging, and cell death. This article is written to provide an overview about the information suggesting significant roles of NAD⁺ and NADH in neuronal death in certain neurological diseases. Our latest studies have suggested that intranasal administration with NAD⁺ can profoundly decrease ischemic brain damage. These observations suggest that NAD⁺ administration may be a novel therapeutic strategy for some neurological diseases.     

雌激素对脑缺血保护作用的分子机制

许多临床及基础研究显示雌激素对脑缺血具有保护作用 ,它能通过多种途径增加缺血区的血流量 ,减少再灌注损伤 ,有利于残存的神经元恢复功能。本文主要从分子机制方面阐述 ,雌激素能抑制缺血区肿瘤坏死因子 α(TNF α)等炎性细胞因子及粘附分子的表达 ;能作用于钙通道抑制钙离子超载和兴奋性氨基酸释放 ;诱发BCL 2等抗凋亡蛋白的表达 ,而且各途径之间关系密不可分。明确雌激素对脑缺血保护作用的确切机制 ,将更好地指导其临床应用     

HIF-1活性调节及其在缺血后血管新生中的作用

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是一种由α亚基和β亚基组成的异源二聚体。该文对HIF-1活性表达及其在缺血/缺氧诱发的血管新生中的重要作用做了简要综述。     

盐酸甜菜碱对缺氧小鼠的保护作用

盐酸甜菜碱(betaine hydrochloride,BTH)是枸杞、牛膝等中药的活性成分,已能化学合成.BTH具有表面活性剂作用,对大肠杆菌、金黄色葡萄球菌、白色念珠菌等具有杀灭作用.在体内具有甲基供体作用,能促进脂肪代谢,具有抗脂肪肝、保护肾脏、降血压、抗肿瘤、缓和应激、增进食欲等药理作用,可用于胃酸缺乏、动脉粥样硬化、肝脏疾病、止痛、风湿病、糖尿病等的治疗,也可用作饲料添加剂[1～4].本文观察了BTH对缺氧小鼠模型的保护作用.     

脑缺血再灌注损伤大鼠大脑皮质NR2A及NR2B受体表达变化

目的探讨N-甲基-D-天冬氨酸受体亚单位NR2A/2B表达与缺血再灌注损伤的关系。方法建立局灶性大脑中动脉阻塞大鼠模型观察缺血2 h再灌6～96 h的组织病理学改变,实时荧光定量PCR及Western印迹法测定大脑皮质NR2A/2B mRNA及蛋白表达。结果大鼠缺血再灌注后6 h,皮质开始出现明显病理学改变,12 h可见血管内有淤血,24 h梗死区锥体细胞出现严重的核固缩、核溶解,几乎看不到正常神经元,48 h出现大面积角质化,96 h可见炎症细胞浸润。与假手术组相比,再灌组NR2A/2B mRNA于再灌注6 h即开始一直持续明显下降(P<0.01),再灌12和24 hNR2A/2B mRNA比值均为1∶2,偏离正常的1∶1,48 h两者的表达开始上调,至96 h NR2A/2B mRNA比值达到1∶1;再灌24 h后NR2A蛋白表达显著降低(P<0.05);NR2B蛋白于再灌6 h开始明显降低,一直持续到24 h(P<0.01),48 h开始上调,96 h后蛋白表达接近假手术组水平。结论缺血2 h再灌注24 h后神经元损伤最严重,并与NR2A/2B表达改变存在时间一致性和受体亚型选择性。     

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.     

Neuroprotective effect of taurine against focal cerebral ischemia in rats possibly mediated by activation of both GABAA and glycine receptors

To investigate the neuroprotective effect of taurine and the involved mechanisms, middle cerebral artery occlusion (MCAO) was induced with suture for 2h in rat, and the brain tissue was then reperfused. The infarct volume and cerebral damage area were measured, respectively, with 2,3,5-triphenyltetrazolium chloride (TTC) staining and MRI. Nissl staining was used for histological observation, and immunohistochemistry and Western-blot analysis for detecting the activated caspase-3 expression. Both pre- (200mgkg(-1)) and post-treatment of taurine decreased the neurology deficit score, infarct volume and brain water content. Taurine post-treatment (67, 200 and 600mgkg(-1)) showed a dose-dependent neuroprotective effect. Taurine (200mgkg(-1)) significantly decreased neuronal loss in the cerebral cortex and hippocampus, and reduced the expression of caspase-3 as well. The neuroprotective effect of taurine was partly blunted by strychnine or bicuculline alone, and almost completely blocked by coapplication of both antagonists of glycine and GABA(A) receptors. It is suggested that taurine exerts a neuroprotective role on the brain when administered before or after MCAO. Such effect is possibly mediated by the activation of both GABA(A) receptors and strychnine-sensitive glycine receptors. Moreover, inhibition of caspase-3 expression is involved in this neuroprotective effect. These results imply a potential therapeutic use of taurine for stroke.     

VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins

The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases.     

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Abstract

GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.     

评价脑苷肌肽治疗急性脑梗死的疗效和安全性

随着社会人口老龄化问题加重, 脑卒中发病率逐年上升, 其中缺血性脑卒中占大多数。近年来, 缺血性脑卒中的主要临床治疗方法为溶栓治疗以及机械取栓, 但疗效有限, 许多患者治疗后仍出现严重残疾, 且不能有效地防治缺血造成的脑组织损伤以及神经功能障碍, 其原因可能是缺乏有效的神经保护剂辅助治疗。目前, 大多数神经保护剂在临床试验中疗效结果均不明显。简述近年来针对脑缺血损伤和脑缺血再灌注损伤的神经保护剂的种类, 讨论其出现应用缺陷的原因, 以促进神经保护剂在临床上成功应用, 为未来缺血性脑卒中的治疗研究提供参考。

     

穿心莲内酯对神经退行性疾病的作用及其机制研究进展

氧化应激、线粒体功能障碍以及炎症反应是神经退行性疾病如阿尔兹海默病(Alzheimer's disease,AD)和帕金森病(Parkinson's disease,PD)等发生和发展的关键环节.因此,保护线粒体、缓解氧化应激和抑制炎症对防治此类疾病具有重要意义.穿心莲内酯是穿心莲的主要有效成分,具有较好的抗炎、抗肿瘤...