一氧化氮在神经退行性疾病中的作用:非类固醇性抗炎药的治疗前景(英文)

一氧化氮(nitric oxide, NO)是一类胞内信使。研究表明,神经退行性病人脑组织中催化合成NO的酶的表达水平显著提高,提示NO与神经退行性疾病密切相关。此外,在这些组织中还检测到硝化的蛋白,提示NO在这些组织中具有生物活性。在神经免疫应答中,神经元和胶质细胞(包括小胶质细胞和星形胶质细胞)内都发生了NO水平的改变。很多神经退行性疾病都伴随有神经炎症,抑制神经炎症的信号通路能延迟这些疾病的发展。因此,NO及其释放通路已逐渐成为神经退行性疾病研究领域的热点,对它们的理解能帮助我们找到合适的方案来预防、减缓或者治愈这些疾病。     

端粒-端粒酶在神经退行性疾病中的研究进展

神经退行性疾病多以β-淀粉样蛋白（β-amyloid,Aβ）、α-突触核蛋白（α-synuclein,α-syn）作为生物标记物来辅助临床进行诊断。近年来,人们发现染色体末端的端粒能够作为衡量生物衰老程度的指标,并发现端粒长度、端粒酶活性可能作为评估老年神经退行性疾病发病风险、疾病进展、不良预后的血液标记物,但目前相关国内外研究结果并不具有一致性。了解端粒相关生物标记物在年龄相关疾病中的作用,是可以帮助临床医生更好地了解疾病的发生发展机制。现就端粒-端粒酶系统在神经退行性疾病中的最新研究进展综述如下,以介绍端粒长度、端粒酶活性对神经退行性疾病的影响以及潜在作用机制。     

梓醇在神经退行性疾病中的神经保护作用研究进展

神经退行性疾病（如阿尔茨海默病和帕金森病）,其病理特征是神经元进行性丧失。神经退行性疾病常见于老年人,且发病率逐年上升,给社会及家庭带来沉重负担。梓醇是一种中草药内提取的活性成分,大量的体内外实验研究已证实,梓醇具有抗炎、抗氧化、抗细胞凋亡、促血管生成及神经保护等多种功能,对神经退行性疾病有显著的防治作用,梓醇可能成为一种较理想的神经退行性疾病治疗药物。因此,该文在此基础上就梓醇在神经退行性疾病的作用机制进行综述。     

脑内铁代谢与神经退行性疾病

铁的正常代谢是大脑发挥正常功能的必要因素。近年研究发现,脑内铁的代谢紊乱在阿尔茨海默病、帕金森病等神经退行性疾病的发生发展中起重要作用。本文对脑内铁正常和异常代谢调节情况及其与神经退行性疾病的关系做一综述。     

NADPH氧化酶在神经退行性疾病中的作用

神经退行性疾病与中枢神经系统内的氧化应激、异常蛋白聚集及炎症反应相关。尽管确切的发病机制目前还不清楚,但研究发现NADHP氧化酶(NOX)在神经退行性疾病的发病过程起了重要的作用,可能成为一个新的药物治疗靶点。因此,本文对NOX进行了概述,并探讨了它与神经退行性疾病之间的关系。     

线粒体自噬与神经退行性疾病

<正>线粒体是双层单位膜围成封闭囊状结构的细胞器,通过氧化磷酸化为细胞提供超过90%的能量,被喻为细胞的动力工厂。2005年,Lemasters[1]首次提出线粒体自噬(mitophagy)这一概念,主要指细胞内的线粒体在细胞衰老、活性氧产生过多等刺激下发生去极化损伤,被双层膜结构特异性包裹后与溶酶体融合,最终降解,维持细胞内环境稳定。神经退行性疾病(neurodegenerative disease)是一组由慢性进行性     

雄激素在神经退行性疾病中的神经保护作用

<正>神经退行性疾病(neurodegenerative disease)主要包括阿尔兹海默病(Alzheimer's Disease,AD)、帕金森病(Parkinson'sdisease,PD)和亨丁顿病(Huntington disease,HD),是一种神经细胞渐进性功能异常并最终导致死亡的疾病。在成年男性,雄激素有助于维持脑的正常功能。男性衰老后,血和脑内睾酮水平均明显下降,睾酮耗竭会引起脑等雄激素敏感的组织功能障碍和疾病。研究表明,睾酮缺乏可增加AD的发病率。2006年,研究人员发现,退行性疾病病人存在睾酮缺     

外泌体在神经退行性疾病发病中的研究进展

外泌体是一种纳米级双层脂质囊泡,它通过主动分选机制包裹特定细胞内容物,包括多种特异性蛋白质、脂质和核酸,靶向作用于受体细胞,参与细胞间信息交流。研究发现,神经元及神经胶质细胞均可释放外泌体,并参与阿尔兹海默病、帕金森病、肌萎缩侧索硬化等神经系统疾病中细胞间物质传递及信息交流。     

ERK蛋白在神经退行性疾病中的研究

神经退行性疾病(neurodegenerative diseases,NDs)是指随着年龄增长逐渐出现的由神经元坏死或功能丧失导致的神经功能障碍,不同病理机制下表现出不同类型的临床病症[1].可能的原因包括蛋白酶体功能障碍、自噬缺陷、氧化应激、线粒体失调、兴奋性毒性和神经炎症等[2].随着人均寿命的增加、医疗环境的改善...     

Pin1在神经退行性疾病中的分子机制

Pin1（peptidylprolyl cis/trans isomerase NIMA-interacting 1）为脯氨酸肽酶异构酶的亚类,是一种催化蛋白质中磷酸化丝氨酸（苏氨酸）―脯氨酸基序之间的肽键异构化酶,具有调节蛋白质折叠、细胞内信号转导、转录、细胞凋亡等功能。Pin1在中枢和周围神经系统中广泛表达,可调节各种神经元发育、凋亡和突触活动。尽管有研究报道,Pin1与神经元底物相互作用影响特定的信号通路,但在神经元水平的生物学功能仍缺乏更全面的了解。此外,越来越多的证据表明,Pin1在衰老及与年龄相关的神经退行性疾病（包括阿尔茨海默病、帕金森病、额颞痴呆、亨廷顿病和肌萎缩侧索硬化）中发挥着至关重要的作用,在这些疾病中,其介导了从神经保护到神经毒性的截然不同的作用。因此,进一步研究Pin1在神经元中的生物学功能,明确Pin1在年龄相关和神经退行性疾病中的分子机制,可为临床治疗相关疾病提供分子靶点。 [国际神经病学神经外科学杂志, 2023, 50(2): 67-70]     

一氧化氮／一氧化氮合酶与神经创伤

一氧化氮是一种简单的气体分子,可在哺乳类神经细胞内经一氧化氮合酶作用产生。ＮＯ在神经创伤修复中的多重作用近年来已受到越来越多的重视。本文对ＮＯ／ＮＯＳ与神经创伤和再生之间的关系作一综述。     

Nitric oxide and nitric oxide synthase in Huntington's disease

Nitric oxide (NO) is a biologically active inorganic molecule produced when the semiessential amino acid l-arginine is converted to l-citrulline and NO via the enzyme nitric oxide synthase (NOS). NO is known to be involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission, neuromodulation, and inflammation, to name only a few. During neuropathological conditions, the production of NO can be either protective or toxic, dependent on the stage of the disease, the isoforms of NOS involved, and the initial pathological event. This paper reviews the properties of NO and NOS and the pathophysiology of Huntington's disease (HD). It discusses ways in which NO and NOS may interact with the protein product of HD and reviews data implicating NOS in the neuropathology of HD. This is followed by a synthesis of current information regarding how NO/NOS may contribute to HD-related pathology and identification of areas for potential future research.     

Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration

The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.     

NADPH-diaphorase/nitric oxide synthase containing neurons in normal and Parkinson's disease putamen

Summary Nitric oxide (NO) is thought to be involved in neurodegenerative processes. Concerning Parkinson's disease (PD) it remains to be elucidated, if NO contributes to pathological alterations in the striatum. The present study evaluates the post-mortem putamen of PD patients and control subjects for distribution patterns of NO-synthase containing neurons, using the NADPH-diaphorase technique. The ratio of positively stained neurons and the total number of cells (control: 1,120±69 per mm², n=5; PD: 575±164mm², n=5) shows striking differences between controls and PD patients. Our findings give reason to conclude that NADPH-diaphorase positive structures may have pathogenetic importance in degenerative processes in PD putamen.     

Nitric oxide synthase does not mediate neurotoxicity after an i.c.v. injection of streptozotocin in the rat

Summary. In the present study we evaluated the possible role of nitric oxide (NO) in mediating neuronal damage in middle-aged rats after an i.c.v. injection of streptozotocin (STREP). An i.c.v. injection of STREP has been reported to decrease the central metabolism of glucose. This inhibition of the energy metabolism after STREP treatment might induce an excitotoxic mechanism, which may lead to the stimulation of NO synthase and, consequently to the synthesis of NO. On the other hand, STREP might induce oxidative stress directly by liberation of NO from its nitroso moiety. To investigate whether NO synthase is involved in a possible excitotoxic mechanism after STREP treatment, some of the rats treated with STREP (1.25 mg/kg in 4 μl, bilaterally 2 μl/injection site) were also treated with the NO synthase inhibitor N-nitro-l-arginine methyl ester (l-NAME, 20 mg/kg i.p. 10 min, 6, 24 and 96 h after STREP injection). To investigate whether NO liberated from STREP may be responsible for neurotoxic effects, one additional group of control rats received an i.c.v. injection of the NO donor sodium nitroprusside (SNP, 10 μg in 4 μl). We found that STREP affected the behavioral performances in the open field and two-way active avoidance task. In addition, immunostaining for glial fibrillary acidic protein, an indicator of reactive astroglial changes to neuronal damage, showed that this was mainly located in peri- and paraventricular regions of the third and lateral ventricles, like for instance in the septum, caudate putamen and hippocampus. l-NAME treatment had no protective effect on the behavioral impairments and neuronal damage of STREP-treated rats. This suggests that the neuronal damage of STREP may still be a result of the decrease in the central energy metabolism, but without the involvement of NO synthase. This was supported by measuring, using immunostaining, the NO-mediated cyclic GMP production by the enzyme soluble guanylyl cyclase in cortical slices, i.e. l-NAME did not prevent NO production after STREP administration in vitro. In addition, it was found that SNP liberated NO in vitro, whereas in vivo SNP administration did not lead to any behavioral and neuronal deficits at all. However, the present study cannot exclude the involvement of NO liberated from STREP in neuronal damage. Received June 7, 1999; accepted September 30, 1999     

偏侧帕金森病猴模型黑质和纹状体一氧化氮合酶表达的变化

目的探讨偏侧帕金森病（PD）猴模型黑质和纹状体一氧化氮合酶（NOS）表达的变化。方法对3只恒河猴经单侧颈内动脉注射1-甲基4-苯基1,2,3,6-四氢吡啶（MPTP）制备成偏侧PD猴模型后,应用还原型尼克酰胺腺嘌呤二核苷酸-黄递酶（NADPH．d）组化染色方法观察偏侧PD猴黑质和纹状体NOS阳性神经元表达的变化,并与正常猴比较。结果偏侧PD猴MPTP毁损侧的黑质和纹状体的NOS阳性神经元数目较毁损对侧和正常猴明显增加（均P〈0．01）,毁损对侧的黑质和纹状体NOS阳性神经元数目与正常猴比较差异无统计学意义。结论偏侧PD猴黑质和纹状体NOS阳性神经元增多,由此引起一氧化氮（NO）合成和释放增多,可能对黑质和纹状体神经元的变性和死亡起重要作用。     

Nitric oxide synthase in cerebral ischemia

The results of our continuing studies on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage as well as related reports from other laboratories are summarized in this paper. Repetitive ip administration ofN ^G-nitro-L-arginine (L-NNA), a NO synthase (NOS) inhibitor, protected against neuronal necrosis in the gerbil hippocampal CA1 field after transient forebrain ischemia with a bell-shaped response curve, the optimal dose being 3 mg/kg. Repeated ip administration of L-NNA also mitigated rat brain edema or infarction following permanent and transient middle cerebral artery (MCA) occlusion with a U-shaped response. The significantly ameliorative dose-range and optimal dose were 0.01–1 mg/kg and 0.03 mg/kg, respectively. Studies using a NO-sensitive microelectrode revealed that NO concentration in the affected hemisphere was remarkably increased by 15–45 min and subsequently by 1.5–4 h after MCA occlusion. Restoration of blood flow after 2 h-MCA occlusion resulted in enhanced NO production by 1–2 h after reperfusion. Administration of L-NNA (1 mg/kg, ip) diminished the increments in NO production during ischemia and reperfusion, leading to a remarkable reduction in infarct volume. In brain microvessels obtained from the affected hemisphere, Ca²⁺-dependent constitutive NOS (cNOS) was activated significantly at 15 min, and Ca²⁺-independent inducible NOS (iNOS) was activated invariably at 4 h and 24 h after MCA occlusion. Two hour reperfusion following 2 h-MCA occlusion caused more than fivefold increases in cNOS activity with no apparent alterations in iNOS activity. Thus, we report here based on available evidence that there is good reason to think that NOS activation in brain microvessels may play a role in the cellular mechanisms underlying ischemic brain injury.     

依达拉奉对帕金森病大鼠模型的神经保护作用及黑质纹状体丙二醛和一氧化氮水平的影响

目的 探讨依达拉奉对帕金森病(PD)大鼠的神经保护作用及黑质纹状体丙二醛(MDA)和一氧化氮(NO)水平的影响.方法 将72只SD大鼠随机分为正常对照组(n=12)、生理盐水对照组(NS组,n=12)、依达拉奉治疗组(ED组,n=48),ED组又分为ED 0.3 mg、1 mg、3 mg及3 mg停药后亚组,每个亚组12只大鼠.在大鼠脑内注入6-羟基多巴胺(6-OHDA)制作PD模型,术后各组大鼠分别相应给予NS 1 ml及ED 0.3 mg/kg、1 mg/kg、3 mg/kg腹腔注射,每天2次,连续14 d.对各组大鼠并进行旋转试验;用免疫组化染色检测黑质酪氨酸羟化酶(TH)阳性细胞数,化学比色法检测黑质纹状体MDA和NO水平.结果 正常对照组大鼠旋转圈数与NS组及ED各亚组比较,差异有统计学意义(均P＜0.01).ED 3 mg及ED 3 mg停药后亚组的旋转圈数显著少于NS组及ED 0.3 mg、1 mg亚组(均P＜0.05).NS组及各ED亚组左侧黑质TH阳性神经元显著少于正常对照组及右侧(均P ＜0.05).ED 3 mg及ED 3 mg停药后亚组左侧黑质TH阳性神经元显著多于NS组和ED 0.3 mg、1 mg亚组(均P＜0.05).与正常对照组比较,NS组和各ED亚组黑质、纹状体NO和MDA水平显著升高(均P＜0.01).ED 3 mg及ED 3 mg停药后亚组黑质、纹状体NO和MDA水平较NS组和ED 0.3 mg、1 mg亚组显著降低(均P＜0.05).结论 依达拉奉对PD大鼠的神经保护作用呈剂量依赖性;其能抑制过氧化反应,降低PD大鼠黑质纹状体的MDA、NO水平.