肾素-血管紧张素系统与阿尔茨海默病

肾素-血管紧张素系统(RAS)是一循环内分泌系统,脑内存在RAS活性,目前关于RAS在脑内定位、以及与阿尔茨海默病(AD)相关的遗传学和分子生物学研究已取得了一定进展。文章综述了RAS与AD的关系,并从血管紧张素转化酶抑制剂(ACEI)、血管紧张素II受体1阻滞剂(ARB)类降压药物在AD中的临床应用等方面总结了RAS在AD中的研究进展。     

血管紧张素Ⅳ：治疗阿尔茨海默病的潜在靶点

诸多证据提示脑内肾素-血管紧张素系统（RAS）与阿尔茨海默病（AD）有着密切关系.血管紧张素Ⅳ（AngⅣ）作为脑内RAS的成员之一,能促进乙酰胆碱释放,抑制胰岛素调节性氨基肽酶（IRAP）,从而减少其对促认知神经肽的降解,同时增强神经元对葡萄糖的摄取和利用,进而提升动物的学习记忆能力,有望成为治疗AD相关认知功能障碍的新靶点.文中就AngⅣ和IRAP的生理学特性、与认知功能的关联以及临床应用所面临的问题进行综述.     

肾素-血管紧张素系统干预与阿尔茨海默病

阿尔茨海默病(AD)是一种以β淀粉样蛋白异常沉积和tau蛋白异常磷酸化为典型病理学改变的神经退行性疾病,是最常见的痴呆类型。肾素-血管紧张素系统(RAS)为体内重要的心血管调节系统,近来研究证实脑内存在独立的RAS;自从研究发现血管紧张素转换酶(ACE)基因多态性与AD发病相关以来,RAS与AD神经生理学关系得到进一步深入研究,越来越多的研究也进一步证实了RAS影响AD的发病和进展。     

中枢血管紧张素的作用

肾素一血管紧张素系统 ( renin-angiotensin system,RAS)在机体的心血管活动和水电解质平衡的调节中起十分重要的作用。近年来随着分子生物学的发展 ,发现 RAS不仅存在于循环中 ,在许多器官如脑、心、血管等中 ,还存在独立的 RAS[1 ,2 ]。脑 RAS不仅调节脑血管收缩 ,脑局部水电解质平衡 ,还通过自分泌和旁分泌作为神经递质和神经调节因子发挥作用。血管紧张素 II( angiotensin II,Ang II)是 RAS的主要活性肽 ,其作用于 Ang II受体 ( angiotensinreceptor,ATR) ,产生已知的全部生物学效应。1　 ATR的分类及其特点Ang II的各种…     

肾素-血管紧张素系统阻断药物在抗高血压治疗中的应用

过去20余年，肾素-血管紧张素一醛固酮（renin-angiotensin-aldosteron，RAA）系统被认为在高血压、心血管疾病和心。肾疾病的发病中占有重要地位。而。肾素一血管紧张素一醛固酮轴已变为药理学干预的重要靶点，其中积累最多的药物治疗经验当首推血管紧张素转换酶抑制药（ACEI）。1981年问世的血管紧张素转换酶抑制药卡托普利（captopril）以其抑制转换酶使血管紧张素Ⅰ（AngⅠ）不能转变为血管紧张素Ⅱ（AngⅡ），从而达到降低血压的目的而受人瞩目。如今被认可的血管紧张素转换酶抑制药已有10种（表1）。其后，1995年首次公布的血管紧张素Ⅱ受体阻断药（angiotensin Ⅱ receptorblocker，ARB）氯沙坦（losartan）以其对肾素-血管紧张素-醛固酮轴新的干预靶点而受到医学界的关注，近年来对血管紧张素Ⅱ受体阻断药的开发更为迅速。此外，这类药物还被确认具有降低血压以外的靶器官保护作用，尤其是具有延缓进行性心、肾血管性疾病的病程，从而使其临床应用适应证从高血压扩展到充血性心力衰竭、心肌梗死后和糖尿病性。肾病等领域。笔仅对目前最常用的肾素-血管紧张素系统（renin—angioten-sinsystem，RAS）阻断药在高血压治疗中的应用进行阐述，而对于醛固酮及阻断其受体的药物则归于利尿药中叙述。     

血管紧张素Ⅳ与认知损害的相关研究进展

血管紧张素Ⅳ作为肾素血管紧张素系统中的一种重要内生肽，与认知功能密切相关。其可通过增强和诱导海马长时程增强、促进葡萄糖转运进入神经元、促使乙酰胆碱释放、刺激一氧化氮生成等方式改善认知损害。文中主要详述血管紧张素Ⅳ及其受体的生理学特性、参与认知功能的作用和机制及其衍生物作为治疗认知损害潜在靶点的前景。     

血管紧张素-(1-7)对大鼠脑缺血再灌注损伤后核因子-κB及下游炎症因子的调控作用

目的 探讨血管紧张素-(1-7)[Ang-(1-7)]对大鼠脑缺血再灌注损伤后核因子-κB(NF-κB)及其下游炎症因子的调控作用. 方法 将42只SD大鼠按随机数字表法分为假手术组、缺血组及Ang-(1-7)治疗组,每组各14只.缺血组及Ang-(1-7)治疗组均行大脑中动脉栓塞术(MCAO).用微型渗透泵分别给予假手术组及缺血组人工脑脊液(aCSF)0.5 μL/h治疗,给予Ang-(1-7)治疗组Ang-(1-7)(100 pmol/L,0.5 μL/h)治疗.脑缺血再灌注损伤后24 h用Western blotting法检测各组大鼠缺血侧皮层细胞核内NF-κB p65蛋白的表达,免疫组化染色检测NF-κB p65的空间分布以及阳性细胞数,酶联免疫吸附测定(ELISA)法测定血清肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)含量. 结果 Ang-(1-7)治疗组缺血侧顶叶皮层细胞核内NF-κB p65蛋白较缺血组降低约46％,差异有统计学意义(P＜0.05).Ang-(1-7)治疗组缺血侧皮层细胞NF-κB p65由胞浆向胞核的移位被显著抑制,NF-κB p65阳性表达率较缺血组降低约29％,差异有统计学意义(P＜0.05).Ang-(1-7)治疗组缺血侧皮层炎症因子TNF-α、IL-1β的表达[(71.603±18.539) pg/mL、(44.648±10.387) pg/mL]较缺血组[(104.763±24.412) pg/mL、(64.787±14.441) pg/mL]均有所降低,差异有统计学意义(P＜0.05). 结论 Ang-(1-7)能显著减轻脑缺血再灌注损伤中的炎症反应,其可能通过作用于Mas受体或拮抗血管紧张素Ⅱ的促炎作用,进而减轻氧化应激反应而实现.     

血管紧张素-(1-7)对大鼠局灶性脑缺血再灌注损伤的神经保护作用

目的 探讨血管紧张素-(1-7)[Ang-(1-7)]对大鼠局灶性脑缺血再灌注损伤的保护作用.方法 对Sprague-Dawley(SD)大鼠制备大脑中动脉梗死(MCAO)模型和假手术模型,并于再灌注24 h和48 h以微型渗透泵从侧脑室给予Ang-(1-7)(100 pmol,0.5 μL/h)或人工脑脊液(aCSF)(0.5 μL/h),由此分组为假手术组(假手术+aCSF)、Ang-(1-7)治疗组[MCAO+Ang-(1-7)]和aCSF治疗组(MCAO+aCSF).检测实验大鼠神经功能评分、再灌注48 h后脑水肿以及再灌注24 h后脑梗死体积,并以试剂盒测定再灌注24 h和48 h后缺血脑组织中超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量,以原位末端标记法(TUNEL)检测再灌注48 h后脑梗死灶周围组织神经细胞凋亡数.结果 Ang-(1-7)治疗MCAO模型大鼠,能显著改善神经功能评分(P<0.05)、缩小脑梗死体积(P<0.05)、降低组织MDA含量(P<0.05)、提高组织SOD活性(P<0.01),并明显减少脑梗死灶周围组织神经细胞凋亡数(P<0.01),但对脑组织含水量无明显影响作用.结论 Ang-(1-7)可能通过抗氧化应急反应、减轻神经细胞凋亡程度等实现治疗缺血再灌注损伤、神经保护作用.     

急性脑血管病并发或不并发多脏器功能失常综合征血浆肾素、血管紧张素、醛固酮的动态变化研究

为了探讨肾素-血管紧张素-醛固酮系统(RAAS)在急性脑血管病(ACVD)及其并发多脏器功能失常综合征(MODS)发生发展中的病理作用机制,动态测定了53例ACVD并发或不并发MODS患者血浆肾素(PRA)、血管紧张素-Ⅱ(AT-Ⅱ)、醛固酮(ALD)的含量变化.     

血管紧张素转换酶基因插入/缺失多态性及与认知功能的关系

血管紧张素转换酶(ACE)通过肾素-血管紧张素系统(RAS)和激肽系统参与心脑血管及中枢神经系统的调节,ACE基因插入/缺失(I/D)多态性与ACE的活性密切相关,而ACEI/D多态性与ACE也参与了认知过程的调节,众多研究探讨了ACEI/D多态性与认知功能的相关关系,但结论不一致,本文就ACE基因及与认知功能的相互关系进行了阐述。     

Glial endocannabinoid system in pain modulation

Pain is affecting the human for centuries and there still is no satisfactory strategy for patients suffering pain particularly chronic pain although intensive studies about its mechanism have been performed in order to improve the treatment of pain. Cannabinoid is a group of chemicals extracted from plants and has a long history in treating pain through the endogenous cannabinoid receptor in the body; however, its application in pain treatment is limited due to its inverse effects. Recent studies have indicated that glial cells play critical role in mediating pain processing through multiple pathway, including excitatory and inhibitory neurotransmission in different levels of the nervous system. Furthermore, the glial cells are found to express cannabinoid receptors. This review summarized the recent studies about the cannabinoid system in glial cells, which may provide some insight for the studying of pain.     

Morphological and biochemical changes in the cholinergic and monoaminergic systems in Alzheimer-type dementia

Summary The integrity of cholinergic and monoaminergic neuronal systems in Alzheimer-type dementia (ATD) was studied using a combination of morphological and biochemical procedures applied to samples from seven ATD brains and ten control brains. On morphological examination, the number of neurons was counted in the nucleus basalis of Meynert (nbM), the locus coeruleus (LC) and the nucleus centralis superior (NCS). Biochemically, the activities of choline acetyltransferase (ChAT) and the concentrations of noradrenaline (NA) and serotonin (5-hydroxytryptamine; 5-HT) were measured in the nbM, LC, NCS, frontal cortex, temporal cortex and occipital cortex. Compared with the controls, the mean number of neurons in the nbM and LC were significantly reduced in the ATD brains. The neuronal loss in the NCS in the ATD brains was not significant. The ChAT activities in all regions from the ATD brains had a tendency to be reduced. Marked reductions in the NA concentrations in the LC and 5-HT concentrations in the temporal and occipital cortices were found in the ATD brains. These findings suggest that various neurotransmitter systems, including cholinergic, noradrenergic and serotonergic systems, are affected in the ATD brains.     

Evidence for modulation of opioidergic activity in central vestibular processing: A [18F] diprenorphine PET study

Animal and functional imaging studies had identified cortical structures such as the parieto‐insular vestibular cortex, the retro‐insular cortex, or the anterior cingulate cortex belonging to a vestibular cortical network. Basic animal studies revealed that endorphins might be important transmitters involved in cerebral vestibular processing. The aim of the present study was therefore to analyse whether the opioid system is involved in vestibular neurotransmission of humans or not. Changes in opioid receptor availability during caloric air stimulation of the right ear were studied with [¹⁸F] Fluoroethyl‐diprenorphine ([¹⁸F]FEDPN) PET scans in 10 right‐handed healthy volunteers and compared to a control condition. Decrease in receptor availability to [¹⁸F]FEDPN during vestibular stimulation in comparison to the control condition was significant at the right posterior insular cortex and the postcentral region indicating more endogenous opioidergic binding in these regions during stimulation. These data give evidence that the opioidergic system plays a role in the right hemispheric dominance of the vestibular cortical system in right‐handers. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

大鼠免疫细胞及器官的固有胆碱能系统

目的探讨大鼠免疫细胞及免疫器官“固有胆碱能系统”的存在状态。方法用免疫荧光双标记、流式细胞技术及免疫组织化学技术,检测烟碱样乙酰胆碱受体α7亚单位(nAChRα7)和胆碱乙酰转移酶(ChAT),乙酰胆碱酯酶(AChE)在健康大鼠外周血CD4+T细胞、腹腔巨噬细胞、关节滑膜巨噬细胞及腹腔淋巴结的表达状态。结果nAChRα7、ChAT及AChE在大鼠免疫细胞及免疫器官均有阳性表达。腹腔巨噬细胞、淋巴结中的巨噬细胞和关节滑膜巨噬细胞表达最丰富,而腹腔淋巴结中的淋巴细胞仅有微弱表达;外周血CD4+T细胞有部分表达(nAChRα7 15.88%±0.753%,ChAT 23.09%±0.671%)。结论免疫活性细胞及免疫器官普遍存在“固有胆碱能系统”,淋巴细胞与巨噬细胞在机体固有胆碱能系统中扮演不同角色。     

Afferent and efferent connections of the primary octaval nuclei in the clearnose skate, Raja eglanteria

Horseradish peroxidase techniques were employed to trace the central projections of afferents from the individual endorgans of the membranous labyrinth and to delineate the efferent projections from the primary octaval nuclei to the spinal cord and midbrain octavolateralis area in the clearnose skate, Raja eglanteria. First-order octaval afferents project ipsilaterally to five primary octaval nuclei, namely: magnocellular, descending, posterior, anterior, and periventricular. Octaval afferents also terminate in the reticular formation, nucleus intermedius (primary mechanoreceptive lateral-line nucleus), and vestibulolateral lobe of the cerebellum. Each primary octaval nucleus receives afferent input from each labyrinthine endorgan, with the possible exception of macula neglecta input to the magnacellular nucleus. Within the anterior, descending, and to a lesser extent posterior and magnocellular nuclei, this input is largely nonoverlapping. Semicircular canal cristae afferents terminate ventrally, saccular and lagenar afferents dorsally, utricular afferents laterally, and macular neglecta afferents course ventrally but terminate largely dorsally within these nuclei. In the vestibulolateral lobe of the cerebellum, cristae afferents project primarily to the pars medialis, whereas macular endorgan afferents terminate in the pars lateralis. Primary afferent input to the reticular formation is predominantly from the horizontal canal crista. The densest projections to nucleus intermedius are from the utriculus and sacculus. Vestibulospinal projections originate primarily from the magnocellular and descending nuclei. Second-order auditory neurons are most likely located in dorsomedial parts of the descending and anterior nuclei. Cells in these nuclei project directly to the auditory area of the midbrain octavolateralis complex, but projections to this area originate predominantly from nuclei C1 and C2, which are possible superior olivary homologues.     

An anatomical and electrophysiological study of the centrifugal visual system in the lamprey (Lampetra fluviatilis)

The centrifugal visual system of the lamprey Lampetra fluviatilis was investigated using various neurohistophysiological methods: intraocular injections of [³H]adenosine, fluorescent tracer (Evans Blue) and the iontophoretic deposit of HRP on the optic nerve. Retrogradely labeled neurons were identified bilaterally within the nucleus M5 of Schober and contralaterally in the reticular mesencephalic area (RMA). Comparison of the various orthograde and retrograde labeling results indicated that the neurons of M5 and RMA were labeled via retrograde axonal transport of the different tracers in the retinopetal system and not by orthograde transneuronal processes or from extraretinal pathways. Part of the anatomical data regarding RMA as a site of origin of the centrifugal visual system was confirmed using electrophysiological techniques involving evoked potential and unit cell recordings in RMA following electrical stimulation of the optic nerve. The experiments were performed in the curarized animal under conditions of either normal blood circulation perfusions of adapted physiological saline, or with a solution known to block chemical synaptic transmission. Various electrophysiological criteria, including the results obtained during the conditions of reversible chemical synaptic blockade, indicated that the responses in RMA reflect an antidromic process. The anatomical organization of the centrifugal visual system in the lamprey is compared to that found in different gnathostome vertebrate species. Several hypotheses concerning the marked interspecies differences related either to the number and the topographical location of the centrifugal neurons as well as the evolution of this system are advanced.     

Enteric origin of bombesin immunoreactive fibres in the rat coeliac-superior mesenteric ganglion

Bombesin-like immunoreactivity occurs in a dense network of nerve fibres in the rat coeliac-superior mesenteric ganglion. No bombesin immunoreactive cell bodies have been observed in this ganglion. An origin outside the ganglion was therefore assumed for the bombesin immunoreactive fibres. Ligation of the mesenteric nerve, between the ganglion and the gut resulted in an accumulation of bombesin immunoreactive material on the distal side, i.e. towards the gut. Transection of the nerve caused a depletion of bombesin immunoreactive fibres in the ganglion. These results suggest that bombesin immunoreactive fibres in the coeliac-superior mesenteric ganglion of the rat originate in neurons in the gastrointestinal wall. Application of colchicine to the stomach wall caused an accumulation of bombesin immunoreactive material in myenteric neurons.     

Soybean agglutinin binding by primary olfactory and primary accessory olfactory projections in different frogs

Comparing eight species of frogs adapted to habitats ranging from aquatic to arboreal, we observed differences in the affinity of primary olfactory projections to the lectin ‘soybean agglutinin’. Particularly pronounced differences exist between Pipa, a frog that rarely leaves the water, and Eleutherodactylus, an arboreal species that does not even utilize aquatic environments for reproduction. We interpret these differences as reflecting specializations to the perception of air-borne vs. water-borne odors.