胰岛素样生长因子1及其代谢物环状甘氨酸-脯氨酸与中枢神经系统疾病

随着人口老龄化的出现,各种神经系统疾病的发病率正在迅速增加。神经营养因子一直是改善老年神经系统疾病的基础和临床研究的重点。胰岛素样生长因子1(IGF-1)是一种神经营养因子,在大脑的细胞增殖、分化、修复和再生中发挥重要作用。最近的研究发现一种IGF-1的代谢物——环状甘氨酸-脯氨酸（cGP）,当IGF-1功能不足时,其可增加IGF-1的生物利用率,从而使IGF-1发挥更有效的神经保护作用。c GP在诊断和治疗中枢神经系统疾病方面发挥重要作用,对中枢神经系统疾病的诊断和治疗具有重要意义。     

胰岛素样生长因子-1与创伤性脑损伤

胰岛素样生长因子-1(IGF-1)是一种脑保护因子,它对神经系统的生长、发育及损伤后的保护具有重要的意义。正常脑组织中IGF-1系统的表达十分广泛,脑损伤后IGF-1在脑内的含量及分布均发生明显变化,显示其参与了脑损伤的病理生理过程,体内、外实验也充分证实IGF-1具有明显的神经保护作用。探讨IGF-1给药的途径和剂量,将为创伤性脑损伤(TBI)的治疗开辟一条新途径。     

胰岛素样生长因子-1与癫痫相关性的研究进展

癫痫是神经系统常见疾病之一,癫痫发作可导致脑损伤已被动物实验和临床观察证实。 胰岛素样生长因子-1（IGF-1）是神经营养保护因子,在中枢神经系统的生长、发育、分化、损伤后修复中 起到重要作用,然而它在癫痫发作中所起的作用存在争议,现回顾目前IGF-1 与癫痫相关研究,对IGF-1 与癫痫关系进行系统综述。     

神经损伤对骨代谢影响的实验研究

目的 通过对90只大鼠神经损伤后,IGF-1（胰岛素样生长因子-1）和NGF（神经生长因子）对骨代谢变化的研究,探讨神经系统影响骨代谢的可能机制。方法 90只实验大鼠随机分为中枢损伤组（脊髓横断）30只,周围神经损伤组（坐骨神经和股神经离断）30只,正常对照组30只。每组又根据7、21、42d不同时间段分为3个亚组．每组10只。结果 神经损伤组后不同时间段血钙、血碱性磷酸酶（ALP）、尿钙（Ca）和尿肌苷（Cr）及Ca／Cr均发生明显改变,骨IGF-1和NGF含量与神经损伤明显相关,且呈程度依赖性改变,特别是NGF含量神经损伤组与正常组比较有显著性差异,并呈现动态的“双相增高”现象,其中枢损伤组变化更为显著。结论 神经系统对骨组织内环境调节是多层次、多元和复杂的,IGF-1和NGF作为骨代谢调节中重要的神经肽及营养因子,在骨吸收和骨形成耦联机制中发挥着极其重要的作用,通过课题研究证明,神经系统对骨代谢调节具有重要作用,并为今后进一步建立“神经-内分泌-骨的轴线调节理论”和制定骨相关疾病的治疗与康复措施奠定基础。     

胰岛素样生长因子-1在神经系统变性病中的作用

<正>胰岛素样生长因子-1(Insulin-ike growth factor 1,IGF-1)是一个7. 5 kD a的肽类激素,它主要在肝脏产生,受垂体分泌的生长激素调节。IGF-1在神经的形成和发育过程中起到重要作用。大部分脑内IGF-1被认为是在低密度脂蛋白受体相关蛋白1 (LRP1)和低密度脂蛋白受体相关蛋白2(LRP2)分子的帮助下从血浆中通过血脑屏障转运而来的~([1])。海马的IGF-1水平与血清中IGF-1水平明显相关,提     

1型胰岛素样生长因子受体在髓母细胞瘤细胞增殖中的作用

目的 研究1型胰岛素样生长因子受体(IGF-1R)在髓母细胞瘤中的表达及其对细胞增殖的作用.方法 荧光定量PCR检测髓母细胞瘤肿瘤标本IGF-1R表达,CCK-8法测定IGF-1R特异性阻断剂NVP-ADW742对髓母细胞瘤Doay细胞增殖抑制作用,并检测其对细胞凋亡的影响,Western blot免疫印迹法检测了 AKT磷酸化蛋白表达变化.结果 髓母细胞瘤肿瘤标本中的1GF-1R mRNA的相对含量明显高于低级别星形胶质瘤;NVP-ADW742能通过诱导细胞凋亡抑制Doay细胞的增殖,NVP-ADW742主要是通过卜凋AKT磷酸化蛋白表达而起作用.结论 IGF-IR在髓母细胞瘤的细胞增殖中起着重要作用.     

迟发性运动障碍与IGF-1关系的研究

迟发性运动障碍(Tardive dyskinesia,TD)是精神科常见的一种由长期服用抗精神病药物所诱发的运动系统运动不良,有明显的不可逆性和致残性,发生率高。目前有关迟发性运动障碍的病因学研究包括多巴胺超敏、氧化应激、神经元毒性学说以及基因关联研究等,大都只局限于神经损伤,而相应的神经保护研究很少。胰岛素样生长因子-1(Insulin-like growth factor-1,IGF-1)是一种与机体组织分化、增殖和成熟有关的重要细胞因子。IGF-I具有较强的抗凋亡作用,是一个重要的细胞存活因子;作用包括对神经损害的保护、神经发生、髓鞘形成、突触发生和树突形成。IGF-1在神经损伤后的保护方面发挥着非常重要的作用,以往的研究表明首发精神分裂症患者在抗精神病药物治疗之前就存在糖代谢相关因子IGF-1的异常,精神分裂症伴发TD患者中IGF-1的异常是否并不是由抗精神病药物引起,而是在抗精神治疗之前就存在。通过对IGF-1在TD发生中的保护机制研究,以确定IGF-1异常是TD的内在素质因素,试图提出TD发生的可能预测指标,为TD的早期预防和选择药物治疗靶点提供理论依据。     

IGF-1与血管性痴呆关系的研究进展

血管性痴呆是老年性痴呆的常见病因,是脑血管疾病造成的脑部损伤所致的智力损害.IGF-1属于胰岛素家族,CNS中的IGF-1通过与其受体结合发挥促进神经元分化的作用.血循环和脑中的IGF-1浓度随年龄增长而降低,并与年龄老化产生的智能减退有关.在脑缺血性损伤后,脑组织中IGF-1及其受体表达增加,能减少梗死面积,修复损伤的神经元.血管性痴呆患者组织病理学上有胆碱能活性降低,脑内炎性斑块形成等AD脑特征,IGF-1是脑内胆碱能系统潜在调节因子,并可减弱β淀粉样片断的毒性作用.     

胰岛素样生长因子-1神经保护作用的研究进展

胰岛素样生长因子－1（Insulin-like growth factor-1，IGF-1）是一种与机体组织分化、增殖和成熟有关的重要细胞因子。IGF-1与其受体结合具有促进细胞分化增殖、抑制凋亡和类胰岛素的代谢作用，并还可能与其他神经营养因子协同发挥神经保护作用。其中，IGF-1保护缺血性脑损伤的可能机制有：甘氨酸-脯氨酸-谷氨酸（glycine-proline-glutamate，GPE）对神经细胞的保护作用、抗凋亡作用、阻止L型钙通道的开放、对一氧化氮合酶（NOS）的双重作用以及对抗兴奋性氨基酸的毒性等。随着临床实验的开展，IGF-1有可能作为脑保护剂用于缺血性脑损伤的治疗。     

胰岛素样生长因子-Ⅰ系统和肌萎缩侧索硬化

目的:胰岛素样生长因子-Ⅰ(IGF-Ⅰ)是一种作用于多个组织和器官的多向性蛋白质,具有促进有丝分裂、刺激蛋白质和蛋白多糖的合成、DNA和RNA的合成以及促进细胞增殖和分化的作用。IGF-Ⅰ调节细胞代谢受胰岛素样生长因子结合蛋白(IGFBPs)的调控,通过IGF受体发挥生理作用。肌萎缩侧索硬化(ALS)是一种致死性神经系统疾病,以脊髓、脑干、运动皮层运动神经元逐渐变性丢失为特征。ALS病因不清,目前有许多假说,其中被大多数认可的学说是运动神经元缺乏必需的营养因子,导致神经元变性、丢失以及靶肌肉萎缩。ALS患者的外周和中枢的IGF-Ⅰ系统均有较大改变。IGF-Ⅰ治疗ALS的离体实验和在体实验效果显著,目前多中心正在进行IGF-Ⅰ治疗ALS患者的三期临床试验。     

叶酸受体在中枢神经系统肿瘤中的研究进展

叶酸受体是一种锚着于膜上的糖蛋白,对叶酸具有高度亲和力,在正常组织分布较少,而在多种恶性肿瘤有过度表达,以叶酸受体为作用靶点,使药物与特异性配体结合即可将药物主动靶向肿瘤细胞.本文就叶酸和叶酸受体的组成、生物学特性、在中枢神经系统肿瘤中的分布特点,以及叶酸受体介导主动靶向肿瘤细胞治疗的研究进展进行综述.     

以中枢神经系统脱髓鞘性假瘤为首发表现的多发性硬化一例并文献复习简

多发性硬化是以白质脱髓鞘改变为特点,与遗传易感性、环境因素共同发挥作用的中枢神经系统自身免疫性疾病,为临床常见的脱髓鞘疾病之一。时间和空间多发性是明确诊断的主要依据,症状典型患者诊断依据较为充分,而仅以单个巨大脱髓鞘性假瘤为首发表现的患者临床少见,极易误诊。     

原发性干燥综合征并发中枢神经脱髓鞘与多发性硬化的鉴别研究进展

原发性干燥综合征(Primary Sjogren's syndrome,PSS)是主要累及外分泌腺体的慢性炎症性自身免疫病,临床上除有外分泌腺如唾液腺受损引起口干、眼干外,还可累及多脏器、多个系统.PSS并发神经病变男女比例为3.8∶31[1].PSS可并发中枢神经系统病变(CNS- PSS),多隐匿起病,部分PSS患者以中枢神经系统损害为首发症状[2].     

RNA interference affects tumorigenicity and expression of insulin-like growth factor-1, insulin-like growth factor-1 receptor, and basic fibroblast growth factor-2 in rat C6 glioma cells

BACKGROUND： Human gliomas are more likely to express basic fibroblast growth factor-2 （FGF-2） insulin-like growth factor-1（IGF-1）, and IGF-1 receptor （IGF-1R） than normal brain tissue. These factors activate signal transduction systems of Ras/MAPK and PI3K/Akl, which promote glioma growth. OBJECTIVE： To utilize RNA interference （RNAi） technique to down-regulate FGF-2, IGF-1, and IGF-1R gene expression, and to investigate the effects of these genes on rat C6 glioma cells, as well as the feasibility of RNAi for treating glioma. DESIGN, TIME AND SETTING： This neurooncological, randomized, controlled, in vivo and in vitro experiment, which used RNAi methodology, was performed at the Laboratory of Molecular Biology, Institute of Biochemistry, Chinese Academy of Sciences between August 2005 and February 2008. MATERIALS： Rat C6 cell lines were purchased from Shanghai Institute of Cellular Biology Affiliated to Chinese Academy of Sciences. Small interfering RNA （siRNA） was synthesized by Shanghai GenePharma. Anti-IGF-1, anti-IGF-1R, anti-FGF-2, anti-mouse and anti-rabbit IgG G1-HRP antibodies were provided by Santa Cruz Biotechnology, USA. Four to six week-old BALB/c nude mice were purchased from the Laboratory Animal Center, Chinese Academy of Sciences. METHODS： C6 glioma cells were transfected with siRNA, which was chemically synthesized in vitro to correspond to endogenous FGF-2, IGF-1, and IGF-1R genes. The inhibition ratio of targeting mRNA expression was detected by semiquantitative RT-PCR, and protein expression was determined by Western blot analysis. C6 glioma cell proliferation was observed using a growth curve C6 glioma cell apoptosis rate and cell cycle were detected by flow cytometry. C6 glioma cell growth regression was observed by transwell migration assay. In addition, nude mouse subcutaneous tumor models were used in this study. For studying the anti-tumor effects of IGF-1 and IGF-1R siRNA, two blank control groups, with six mice each, were set up： A （2.5 μg siRNA was injected one week after C6 cells were inoculated, Le., when tumor volume reached 8 mm × 8 mm） and B （siRNA was injected at the same time with C6 cells were inoculated. To study the effects of FGF-2 siRNA, the groups consisted of a blank control group, negative control group, 2.6 μg siRNA group, 4 μg siRNA group, and 5.3 μg siRNA group, with six mice each. MAIN OUTCOME MEASURES： mRNA and protein inhibition ratio of FGF-2, IGF-1, and IGF-1 R; C6 glioma cell proliferation, apoptosis, and cycle growth arrest; C6 glioma cell growth regression and subcutaneous tumorigenicity rates. RESULTS： All siRNA constructs proved to be effective. After 48 hours, transfection of 200 nmol/L siRNA resulted in a FGF-2 or IGF-1R gene inhibition ratio 〉 80% and an IGF-1 gene inhibition ratio of approximately 70%. Protein expression levels for FGF-2, IGF-1, and IGF-1R decreased in a dose-dependent manner following siRNA transfection, with an inhibition rate 〉 85%, 60%, and 50%, respectively. C6 glioma cell proliferation and apoptosis rates increased in proportion to siRNA. The apoptosis rate of C6 glioma cells induced by FGF-2, IGF-1, and IGF-1R siRNA was 39.96%, 15.07% and 22.47%, respectively （P 〈 0.01）. Transfection of 200 nmol/L IGF or IGF-1R siRNA for 48 hours suppressed C6 glioma cell migration. At 30 days after intratumoral injection of 2.6, 4, and 5.3 tJg FGF-2 siRNA, tumor growth regression rate of FGF-2 siRNA was 56%, 67%, and 86%, respectively. The tumor growth regression rate was 71.88% and 45.71%, respectively, when IGF-1 or IGF-1R siRNA was intratumorally injected 1 week after C6 glioma cell transplantation. When IGF-1 or IGF-1 R siRNA was intratumorally injected during C6 glioma cell transplantation, the tumor growth regression rate was 78.13% and 74.29%, respectively. CONCLUSION： siRNA transfection downregulated gene expression of FGF-2, IGF-1, and IGF-1R In addition, siRNA treatment markedly suppressed glioma cell proliferation, growth, and migration, and concomitantly reduced subcutaneous tumorigenicity.     

神经生长因子促再生坐骨神经血管生成的作用

BACKGROUND： It remains to be determined whether nerve growth factor （NGF） can promote angiogenesis in regenerating peripheral nerves during repairing peripheral nerve injury.
OBJECTIVE： To evaluate the effects of NGF on angiogenesis, and to analyze the influencing mechanisms of NGF, according to the expression patterns of CD34, von Willebrand factor （vWF）, vascular endothelial cell growth factor （VEGF）, and the NGF receptor TrkA in proliferating vascular endothelial cells from a rat model of sciatic nerve injury.
DESIGN, TIME AND SETTING： Randomized, controlled study performed at the Research Institute of Field Surgery, Daping Hospital affiliated to the Third Military Medical University of Chinese PLA, between October 2003 and July 2005.
MATERIALS： Forty-five healthy, adult, Wistar rats underwent sciatic nerve injury. The rats were randomly divided into four groups： NGF ＋ chitosan （n = 15）, NGF ＋ chitosan ＋ anti-VEGF （n = 10）, chitosan （n = 10）, and physiological saline （n = 10）. METHODS： A 1 -cm defected sciatic nerve was bridged with a silica gel conduit. NGF ＋ chitosan group： 100 μ L chitosan and 5 μ L NGF （20 mg/L） were injected into the silica gel conduit; NGF ＋ chitosan ＋ anti-VEGF group： an additional 5μ L anti-VEGF monoclonal antibody （1 g/L） was injected into the silica gel conduit; chitosan group： 100μL chitosan and 5 μL physiological saline were injected into the silica gel conduit; physiological saline group： only 5μL physiological saline was injected into the silica gel conduit.
MAIN OUTCOME MEASURES： CD34 and vWf were used to label blood capillaries and large-diameter blood vessels in the regenerating peripheral nerves, respectively. At day 14 following surgery, immunohistochemistry was used to detect and semi-quantitatively analyze expressions of CD34, vWf, VEGF, and TrkA in proliferating vascular endothelial cells in the regenerating sciatic nerve. A confocal laser microscope was used to determine co-expression. RESULTS： Expressions of TrkA, CD34, vWf, and VEGF in the NGF ＋ chitosan group were significantly greater than the physiological saline and chitosan groups （P 〈 0.05-0.01）. Expressions of CD34 and VEGF in the NGF ＋ chitosan ＋ anti-VEGF group were completely inhibited, while expressions of vWf and TrkA gradually decreased, compared with the NGF ＋ chitosan group （P 〈 0.01）. Confocal microscopy revealed strong co-expression of VEGF and CD34 in the regenerating sciatic nerve, and CD34 expression positively correlated with VEGF expression. In addition, VEGF expression was greater than CD34 expression, and coexpression of VEGF and vWf was also strong.
CONCLUSION： VEGF was expressed in blood capillaries and large-diameter blood vessels, while exogenous NGF promoted VEGF expression in regenerating sciatic nerves, thereby increasing angiogenesis.     

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.     

缺氧与阿尔茨海默病:低氧诱导因子-1的作用

阿尔茨海默病(Alzheimer's disease,AD)是最常见的老年神经变性疾病,其临床诊疗重视“早期发现、早期诊断、早期治疗”.体液或脑内有特定的AD生化、病理等改变,但未出现临床症状的AD称为临床前期阿尔茨海默病(Preclinical AD,PCAD).确定PCAD的危险因素,并进行早期干预对AD的防治有重要意义.缺氧是临床上常见的疾病病理过程,也是AD等多种神经变性疾病的重要危险因素.缺氧导致AD或促进AD病程进展的可能机制受到了广泛的关注和研究,本文就缺氧导致β-淀粉样蛋白(Aβ)沉积、tau蛋白异常磷酸化和神经元变性死亡的机制进行了综述,着重讨论了低氧诱导因子(hypoxia inducible factor 1,HIF-1)在其中的复杂作用.     

血管内皮细胞生长因子在抑郁症中作用的研究进展

抑郁症是一种发生率和致死率高、易复发的慢性精神疾病,是一种高度遗传异质性疾病,目前具体机制尚不明确。多种因素、信号途径参与了该疾病的病理生理过程,近来多项研究显示血管内皮细胞生长因子（VEGF）参与了抑郁症的病理过程,本文就VEGF在抑郁症中作用的研究进行综述性分析。     

Hippocampal CA1 pyramidal cells and neurotrophic factors in a rat model of vascular dementia following Xiongma drop pill versus Ginkgo leaf tablets

BACKGROUND： Previous studies have demonstrated the neuroprotective effects of Xiongma drop pill （XMDP） in a mouse model of vascular dementia. Neurotrophic factors play an important role in repair and regeneration of injured neurons. OBJECTIVE： To compare the effects of XMDP and Ginkgo leaf tablets on the appearance and number of hippocampal CA1 pyramidal neurons, as well as neurotrophic factor content in brain tissues, during vascular dementia formation to explore the neuroprotective mechanisms of XMDP. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Pharmacology, College of Pharmacy, Harbin University of Commerce between April 2007 and December 2008. MATERIALS： XMDP was prepared by the College of Pharmacy, Harbin University of Commerce, with each 40 mg pill containing ferulic acid （≥ 0.149 mg） and gastrodin （≥ 0.171 mg）. Ginkgo leaf tablets were purchased from Taiyuan Qianyuan Pharmacy, China. METHODS： Healthy, adult, male, Wistar rats were randomly assigned to 6 groups： sham-operation, model, XMDP （high-, middle-, and low- dose）, and Ginkgo leaf tablets. The 6 groups were subdivided into two subgroups according to administration days, i.e., 30 and 60 days, with 8 animals in each subgroup. Rats in the model, XMDP, and Ginkgo leaf tablets groups were subjected to permanent bilateral ligation of the common carotid artery to establish a vascular dementia model. At 8 days after model establishment, all groups received intragastric administration once daily of the following： 10 mL/kg normal saline in the sham-operation and model groups; 0.4, 0.2, and 0.1 g/kg XMDP in the high-, middle-, and low-dose XMDP groups, respectively; and 50 mg/kg Ginkgo leaf tablets in the Ginkgo leaf tablets group. MAIN OUTCOME MEASURES： Hematoxylin-eosin staining was used to observe appearance and to quantify the number of hippocampal CA1 pyramidal neurons. Brain-derived neurotrophic factor and nerve growth factor concentrations in brain tissues were detected by enzyme-linked immunosorbent assay. RESULTS： Following model establishment, hippocampal CA1 neurons exhibited pathological changes. Compared with the sham-operation group, the number of pyramidal neurons significantly decreased （P 〈 0.05 or P 〈 0.01）, and neurotrophic factor concentration increased in the model rats （P 〈 0.05 or P 〈 0.01）. XMDP attenuated neuronal injury in a dose-dependent manner： the number of pyramidal neurons and neurotrophic factor concentrations were significantly increased compared with the model group （P〈 0.05 or P〈 0.01）. High- and middle-dose XMDP resulted in equivalent effects to Ginkgo leaf tablets. In addition, neurotrophic factor concentrations in all XMDP groups, after 60 days of administration, were remarkably greater than corresponding concentrations at 30 days （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Hippocampal CA1 pyramidal cells exhibited pathological injury following establishment of the vascular dementia model. Middle- and high-dose XMDP increased neurotrophic factor expression in the brain of vascular dementia rats, which suggested neuroprotection equivalent to Ginkgo leaf tablets.