神经系统疾病与环核苷酸

环核苷酸是近廿年来生物化学的重要进展之一,1957年研究肾上腺素和胰高血糖素的机理时发现环磷酸腺苷(cAMP),1963年Ashman又检出了环磷酸鸟苷(cGMP).嗣后人们对环核苷酸的基本性质、生物作用、环核苷酸细胞内浓度的调节因素以及cAMp与cGMP的关系作了大量研究,对环核苷酸的生化、生理及药理作用有了进一步了     

精神疾病患者血浆cAMP、cGMP含量的变化

对住院治疗的87例精神疾病患者血浆环磷酸腺苷(cAMP)、环磷酸乌苷(cGMP)的含量进行了测定。旨在探讨cAMP、cGMP在精神疾病的病因、诊断、疗效和转归上的作用及影响。     

环磷腺苷信号通路与血管重塑关系的研究进展

环磷腺苷（cyclic adenosine monophosphate,cAMP）信号通路作为一种重要的细胞内信息传 递系统参与调节了多种生物活动。近期研究发现,cAMP通路的激活可有效抑制心脑血管疾病进程中 的血管重塑,cAMP通路有望成为治疗上述疾病的新的靶目标。本文从cAMP通路抑制血管内皮炎症、 内膜增生和血小板异常激活等方面阐述cAMP信号通路与血管重塑的关系。     

急性脑血管病脑脊液环核苷酸的变化及其临床意义的初步探讨

以放射免疫分析法测定急性脑血管病75例,脑瘤卒中4例的脑脊液环磷酸腺苷(cAMP)与环磷酸乌苷(cGMP),并与22例非神经系统疾病患者作对照。发现cAMP有不同程度的升高,但各病种之间差异不显著。cGMP无明显变化,仅瘤卒中时cGMP显著升高。cAMP浓度与意识障碍及预后有一定关系。     

磷酸二酯酶4在神经系统疾病发病机制中的作用

环磷酸腺苷(cAMP)为哺乳动物的经典第二信使,参与调节其许多生理功能,包括肝脏和肌肉的糖原储存、学习、记忆、心情及情感等[1]。磷酸二酯酶(PDE)4为cAMP特异性的水解酶,其水解活性功能通常占细胞内水解cAMP活性功能的主要地位。PDE4在神经系统的各类细胞中均有不同程度的表达,在调节神经系统活动中起着重要的作用。研究[1]表明,PDE4抑制剂Rolipram和其他典型的抑制剂具有增强意识、抗抑郁、抗焦虑、抗炎症、平滑肌松弛的作用。现对PDE4在神经系统疾病发病机制中的作用综述如下。     

西洛他唑防治脑卒中的研究进展

西洛他唑(CZ)能够提高细胞内环磷酸腺苷(cAMP)水平,并主要由cAMP介导实现抗血小板聚集等作用.研究发现该药能降低脑卒中风险,减少卒中复发,改善卒中患者预后,其有效性和安全性已得到证实.     

松果体、中枢核团与淋巴细胞间信息传递的昼夜节律

目的探讨松果体、中枢核团视交叉上核（SCN）和中缝背核（DR）与外周淋巴细胞之间昼夜节律的联系和传递关系。方法在标准的光照条件下,测定中枢和外周第一信使褪黑素（MT）、第二信使cAMP和cGMP的昼夜节律。结果在小鼠松果体和血清中,MT含量的昼夜节律峰值位于黑暗中期,而各组织中cAMP／cGMP比值的节律峰值却位于光照中期,呈现相互倒置的位相关系。各组织中cAMP／cGMP比值的昼夜节律的峰值分别为：松果体,－155．82°（CT10　：23）;SCN,－166．30°（CT10：54）;DR,－179．16°（CT11：56）;血清,－186．66°（CT12：27）;淋巴细胞,－188．00°（CT12：32）。结论依据cAMP／cGMP峰值出现的昼夜时间先后,由中枢向外周淋巴细胞的信息传递按照松果体→SCN→DR→血液→淋巴细胞的顺序进行。     

肝硬化患者血浆环核苷酸、环鸟苷酸含量的变化

环核苷酸(cAMP)及环乌苷酸(cGMP)是各种动物细胞内具有重要生物效应的物质,肝硬化时,由于其免疫功能失调,肝细胞变性、坏死与增殖,从而影响 cAMP 及 cGMP 的血浆含量。本文对14例肝硬化患者血浆 cAMP 和 cGMP 含量的变化进行了观察并探讨其临床意义。对象和方法1 对象1.1 对照组本院健康献血员19人,男15人,女4人,年龄20～40岁。1.2 肝硬化组皆为本院消化专科住院病人,经检查均确诊为肝硬化者,男12人,女2人,年龄28～55岁。     

神经系统中内源性硫化氢相关生物学功能的研究进展

气体信号分子是生物体及细胞内存在的一种具有独特生物学作用的信号途径,具有连续产生、传播和弥散迅速等特点。该命题是随着20世纪80年代中期发现内源性气体分子一氧化氮(NO)通过一氧化氮合酶作用于精氨酸而产生并与细胞内鸟氨酸环化酶结合从而提高胞内环磷酸鸟苷(cGMP)水平并具有舒张血管、抑制血小板聚集和抑制细胞     

中枢神经再生的分子基础

由于Nogo、髓磷脂相关糖蛋白以及少突胶质细胞-髓磷脂糖蛋白等抑制神经再生因子的发现,对中枢神经系统再生的分子机制研究也有了较大进展,发现这三种结构互不相关的蛋白都通过NgR/p75NTR复合体发挥作用。在细胞内,不管是NgR/p75NTR复合体传导的外源性髓磷脂抑制,还是神经元的内源性再生机制,都要经过Rho的调节,而后者又受到环磷酸腺苷的调节,这条通路目前被认为是中枢神经再生的主要信号传导通路。     

人格特征与疾病关系的研究

人格特征与疾病之间具有紧密联系。本文首先回顾了A型人格与冠心病、C型人格与癌症的相关研究，然后着重介绍了一种新的危险因素——D型人格，并对其与心血管疾病的关系进行了简要论述，最后本文提出了一些干预措施。     

Edema and neuronal apoptosis in the hippocampus and cortex of elderly rats following transient cerebral ischemia/reperfusion injury

BACKGROUND： Previous studies of cerebral ischemia have used young animals, with an ischemic time greater than 5 minutes （safe time limit）. Despite an increased understanding of neuronal apoptosis, it remains uncertain whether brief cerebral ischemic events of 5 minutes or less damage brain tissue in elderly rodents. OBJECTIVE： To investigate the effects of transient cerebral ischemia （5 minutes）/reperfusion injury on brain cortical and hippocampal edema, aquaporin-4 （AQP-4） expression, and neuronal apoptosis in aged rats, and to compare ischemic sensitivity between cortex and hippocampus. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Cerebrovascular Disease, Qingdao University Medical School from April 2008 to March 2009. MATERIALS： Rabbit anti-AQP-4 polyclonal antibody, TUNEL kit, and SABC immunohistochemistry kit were purchased from Wuhan Boster Bioengineering, China. METHODS： A total of 160 healthy, male, aged 19-21 months, Wistar rats were randomly assigned to 4 groups： sham-surgery, and ischemia 1-, 3-, and 5-minute groups, with 40 rats in each group. The global cerebral ischemia model was established using the Pusinelli four-vessel occlusion, and the three cerebral ischemia groups were subdivided into reperfusion 12-hour, 1-, 2-, 3-, and 7-day subgroups, with 8 rats in each subgroup. The sham-surgery group was subjected to exposure of the first cervical bilateral alar foramina and bilateral common carotid arteries. MAIN OUTCOME MEASURES： The dry-wet weight assay was used to measure brain water content and histopathology of the cortex and hippocampus was observed following hematoxylin-eosin staining. In addition, cortical and hippocampal AQP-4 expression was detected by streptavidin-biotin complex immunohistochemistry, and neuronal apoptosis was detected by the TUNEL method. RESULTS： There was no significant difference in brain water content or AQP-4 expression in the cortex and hippocampus between ischemia 1- and 3-minute groups and the sham-surgery group or brain water content or AQP-4 expression in the cortex between ischemia 5-minute group and sham-surgery group （P 〉 0.05）. However, brain water content and AQP-4 expression in the hippocampus after 5 minutes of cerebral ischemia were significantly increased compared with the sham-surgery group （P 〈 0.05 or P 〈 0.01）. Several TUNEL-positive cells were observed in the cortex and hippocampus of the sham-surgery group and ischemia 1-minute group, as well as in the cortex of the ischemia 3-minute group. In addition, the number of apoptotic neurons in the hippocampus of ischemia 3-minute group and in the cortex and hippocampus of ischemia 5-minute group was significantly increased （P 〈 0.05 or P 〈 0.01 ）. Neuronal apoptosis was increased after 12 hours of ischemia/reperfusion, and it reached a peak by 2 days （P 〈 0.01）. CONCLUSION： Transient cerebral ischemia （5 minutes） resulted in increased hippocampal edema, AQP-4 expression, and neuronal apoptosis. Moreover, cerebral ischemia had a greater effect on neuronal apoptosis than brain edema or AQP-4 expression, and the hippocampus was more sensitive than the cortex.     

Upregulation of stromal cell-derived factor-1 alpha/CXCR4 axis-induced migration of human neural progenitors by tumor necrosis factor-alpha and interleukin-8

BACKGROUND： Studies of several animal models of central nervous system diseases have shown that neural progenitor cells （NPCs） can migrate to injured tissues. Stromal cell-derived factor 1 alpha （SDF-la）, and its primary physiological receptor CXCR4, have been shown to contribute to this process. OBJECTIVE： To investigate migration efficacy of human NPCs toward a SDF-1α gradient, and the regulatory roles of tumor necrosis factor-α （TNF-α） and interleukin-8 （IL-8） in SDF-1α/CXCR4 axis-induced migration of NPCs. DESIGN, TIME AND SETTING： An in vitro, randomized, controlled, cellular and molecular biology study was performed at the Laboratory of Department of Cell Biology, Medical College of Soochow University between October 2005 and November 2007. MATERIALS： SDF-1α and mouse anti-human CXCR4 fusion antibody were purchased from R＆D Systems, USA. TNF-αwas purchased from Biomyx Technology, USA and IL-8 was kindly provided by the Biotechnology Research Institute of Soochow University. METHODS： NPCs isolated from forebrain tissue of 9 to 10-week-old human fetuses were cultured in vitro. The cells were incubated with 0, 20, and 40 ng/mL TNF-α, or 0, 20, and 40 ng/mL IL-8, for 48 hours prior to migration assay. For antibody-blocking experiments, cells were further pretreated with 0, 20, and 40 μg/mL mouse anti-human CXCR4 fusion antibody for 2 hours. Subsequently, the transwell assay and CXCR4 blockade experiments were performed to evaluate migration of human NPCs toward a SDF-1α gradient. Serum-free culture medium without SDF-1α served as the negative control. MAIN OUTCOME MEASURES： The transwell assay was performed to evaluate migration of human NPCs toward a SDF-1α gradient, which was blocked by fusion antibody against CXCR4. In addition, CXCR4 expression in human NPCs stimulated by TNF-α and IL-8 was measured by flow cytometry. RESULTS： Results from the transwell assay demonstrated that SDF-1α was a strong chemoattractant for human NPCs （P 〈 0.01）, and 20 ng/mL produced the highest levels of migration. Anti-human CXCR4 fusion antibody significantly blocked the chemotactic effect （P 〈 0.05）. Flow cytometry results showed that treatment with TNF-α and IL-8 resulted in increased CXCR4 expression and greater chemotaxis efficiency of NPCs towards SDF-1α（P 〈 0.01）. CONCLUSION： These results demonstrated that SDF-la significantly attracted NPCs in vitro, and neutralizing anti-CXCR4 antibody could block part of this chemotactic function. TNF-α and IL-8 increased chemotaxis efficiency of NPCs towards the SDF-1αgradient by upregulating CXCR4 expression in NPCs.     

Environmental factors in the development and progression of late-onset Alzheimer＇s disease

Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.     

阿伐他汀对实验性自身免疫性脑脊髓炎免疫功能的影响

目的观察阿伐他汀（Atorvastatin）对EAE的治疗作用并初探其治疗机制。方法以豚鼠脑、脊髓为原料提取髓鞘碱性蛋白MBP,免疫Lewis大鼠建立EAE模型。建模后每日对大鼠神经症状进行评分,采用ELISA法检测大鼠脾细胞培养上清液中IFN-γ、IL-12和IL-4水平。结果与EAE组相比,Atorvastatin组大鼠发病时间有所延迟,症状有不同程度减轻。与正常组相比,EAE组大鼠17d、21d时,IL-4水平明显升高（P〈0．01）,13,17,21d时IFN-γ、IL-12水平均明显升高（P〈0．01）;IFN-γ、IL-12浓度与神经症状评分有较强的正相关关系（RIFN-γ=0．904,P〈0．01;RIL-12=0．885,P〈0．01）。与EAE组相比,Atorvastatin组13d、17d时IL-4水平明显升高（P〈0．01）。IFN-γ、IL-12水平在13,17,21d时均显著低于EAE组（P〈0．05）。结论Alorvastalin能改善EAE大鼠的症状,其机制可能与纠正Th1／Th2失衡有关。     

Astrocyte reactivity in related brain regions in a mouse model of MPTP-induced Parkinson’s disease

BACKGROUND： Severe injury to dopaminergic neuronal cell bodies and their axon terminals in the substantia nigra pars compacta （SNC） has been observed in both Parkinson＇s disease （PD） patients or in 1-methy-4-phenyl-1,2,3,6-tetrahydropyrindine（MPTP）-induced PD animal models, but only slight injury occurs in the adjacent ventral tegmentat area （VTA）. The mechanisms underlying this selective injury remain poorly understood. OBJECTIVE： To comparatively observe astrocyte reactivity in the SNC, caudate putamen （CPu）, VTA, and frontal association cortex （FrA）.
DESIGN, TIME AND SETTING： A cellular and molecular biology, randomized, controlled experiment was performed at the Institute of Neurobiology, Department of Human Anatomy, Medical School of Nantong University, between December 2006 and September 2008.
MATERIALS： A total of 80 healthy adult male C57BL/6 mice were included in this study. MPTP was purchased from Sigma, USA.
METHODS： Mice were randomly divided into a model group （n = 64） and a sham-operated group （n = 16）. PD was induced in the mice from the model group by intraperitoneal injection of 20 mg/kg MPTP, once every three hours, for a total of 4 times.
MAIN OUTCOME MEASURES： Tyrosine hydroxylase （TH）-immunoreactive neurons and glial fibrillary acidic protein （GFAP）-immunoreactive astrocytes were examined by dual immunofluorescence labeling. GFAP-immunoreactive astrocytes in the CPu and FrA were determined by immunofluorescent staining. GFAP mRNA expression in the SNC, CPu, VTA, and FrA was detected using real-time polymerase chain reaction. TH protein levels in the TH-immunoreactive axon terminals of the CPu and FrA were detected by Western blotting.
RESULTS： Numbers of TH-immunoreactive neurons in the SNC, and TH protein level in the CPu, markedly decreased （by approximately 68%） 1 day after MPTP injection, and gradually increased at 3 days. Simultaneously, astrocyte reactivity was strengthened, in particular at 7 days. However, after MPTP injection, decreases in the numbers of TH-immunoreactive neurons in the VTA, and TH protein levels in the FrA, were less apparent （approximately 15%）. Also, no obvious astrocyte reactivity was observed.
CONCLUSION： In a mouse model of PD, astrocyte reactivity was apparent in the SNC and CPu, but not the VTA or FrA. In addition, astrocyte reactivity was greater in regions where injury to dopaminergic neurons was more severe.     

Activation of mammalian target of rapamycin contributes to pain nociception induced in rats by BmK I,a sodium channel-specific modulator

The mammalian target of rapamycin （mTOR） pathway is essential for maintenance of the sensitivity of certain adult sensory neurons. Here, we investigated whether the mTOR cascade is involved in scorpion envenomation-induced pain hypersensitivity in rats. The results showed that intraplantar injection of a neurotoxin from Buthus martensii Karsch, BmK I （10 pg）, induced the activation of mTOR, as well as its downstream molecules p70 ribosomal S6 protein kinase （p70 S6K） and eukaryotic initiation factor 4E-binding protein 1 （4E-BP1）, in lumbar 5-6 dorsal root ganglia neurons on both sides in rats. The activation peaked at 2 h and recovered 1 day after injection. Compared with the control group, the ratios of p-mTOR/p-p70 S6K/p-4E- BP1 in three types of neurons changed significantly. The cell typology of p-mTOR/p-p70 S6K/p-4E-BP1 immuno-reactive neurons also changed. Intrathecal administration of deforolimus, a specific inhibitor of mTOR, attenuated BmK I-induced pain responses （spontaneous flinching, paroxysmal pain-like behavior, and mechanical hypersensitivity）. Together, these results imply that the mTOR signaling pathway is mobilized by and contributes to experimental scorpion sting-induced pain.     

高血压脑出血的显微外科治疗进展

高血压脑出血（Hypertensive intrac-rebral hemorrhage,HICH）是具有高发病率、高病死率、高致残率的急性脑血管疾病,占所有脑卒中患者的10%-20%,早期病死率可高达49.4%。随着人口老龄化,其发病率逐年提高;而外科手术的干预,使其病死率有所下降,但致残率居高不下。如何提高手术疗效和患者生存质量,一直是神经外科医师努力的方向。微侵袭血肿清除术因其手术创伤小,恢复快,是目前国内治疗高血压脑出血的重要手段。     

神经内镜联合亚低温治疗高血压基底节区脑出血

目的 探讨神经内镜联合亚低温在治疗高血压基底节区脑出血中的临床应用价值.方法 回顾性分析我院神经内镜治疗高血压基底节区脑出血患者40例的临床资料,并对治疗结果进行分析.结果 神经内镜治疗组22例(甲组),神经内镜联合亚低温治疗组18例(乙组),术后3个月根据GCS评分,甲组恢复良好1例,中残4例,重残6例,植物生存6例,死亡5例;乙组恢复良好4例,中残8例,重残3例,植物生存1例,死亡2例,两组比较差异有统计学意义(P＜0.05).两组颅内压比较第1天两者差异不明显,但第2、3天亚低温组颅内压明显降低.结论 神经内镜是治疗高血压基底节区脑出血较为有效的手术方式,联合亚低温治疗能有效降低颅内压,改善术后神经功能恢复,具有较好的临床应用价值.