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| 1 | 脑源性神经生长因子促进脑梗死后小鼠内源性神经干细胞的增殖及向神经元分化显示文摘目的:探讨脑源性神经生长因子是否能促进脑梗死后小鼠内源性神经干细胞的活跃,能否刺激其分化成神经元。方法:实验于2004-07/2005-02在墨尔本大学完成。选取10周龄纯种C57BL/6J小鼠24只,分为盐水对照组、脑源性神经生长因子治疗组,每组雌雄各6只。①两组均采用结扎左侧大脑中动脉远心端法建立脑梗死模型,同时采用Matsushita描述的方法监测大脑中动脉供血区的血流量,血流量降低至少75%为有效。②脑源性神经生长因子治疗组于梗死后24h给予脑起源神经营养因子治疗,用药方式采用ALZET锇药物泵缓慢释放。将500μg/kg脑起源神经营养因子溶解于生理盐水中,加入到ALZET泵中,可在28d内持续缓慢释放药物。盐水对照组于梗死后24h给予等量生理盐水。③造模前后对两组小鼠运动功能进行Rotarod测试,记录小鼠在Rotarod上的停留时间。采用双重免疫荧光组化及共焦计数系统检测方法,对两组小鼠内源性神经干细胞的数量、密度及其分化方向进行评估。结果:①运动功能测试结果:与梗死前比较,两组小鼠在梗死后第1周均表现出明显的运动功能下降。但梗死后第2,3,4周,脑起源神经营养因子治疗组小鼠在Rotarod上的停留时间延长,运动功能的恢复明显优于盐水对照组,差异有显著性意义(P<0.01)。②组织切片双重免疫荧光染色结果:两组小鼠脑内均出现免疫荧光阳性表达的内源性神经干细胞,主要分布在病灶周围,在损伤侧的对侧也出现表达。脑起源神经营养因子治疗组的表达数量明显高于盐水对照组。③内源性神经干细胞的激活情况:梗死4周后,两组小鼠脑内都出现内源性神经干细胞的再表达,脑起源神经营养因子治疗组内源性神经干细胞数较盐水对照组明显增加,约4.2倍。同时脑起源神经营养因子治疗组分化为神经元的比例明显高于盐水对照组(36%,15%),分化为星形胶质细胞的比例低于盐水对照组(54%,77%),分化为少突胶质细胞的比例二者基本相似(10%,8%)。结论:脑起源神经营养因子可能是基于内源性神经干细胞治疗脑卒中的一种有效的方法.通过调控内源性神经干细胞的增殖分化来治疗神经系统疾病在未来将是一种新的干细胞治疗方法. | 臧大维 刘娟 左宪华 Surindar Cheema | 2006 | 中国临床康复2006，10，33： | 9 |
| 2 | 脊髓损伤后神经营养因子及干细胞治疗对轴突再生的影响:国外基础和临床研究新进展(英文)显示文摘背景:近几年国外学者在脊髓损伤的病理机制、损伤后神经元的保护、少突胶质细胞的再生及神经干细胞的移植治疗等研究方面取得了实质性地进展。介绍国外近10年来对脊髓损伤的新认识,最新研究成果及未来的科研和治疗方向。资料来源:应6用计算机检索Medline数据库1987-01/2006-10脊髓损伤的相关文章,限定文章语言种类为English,检索词为“脊髓损伤;神经干细胞;轴突;神经营养因子;动物模型”,进行不同组合,选出相关文章。资料选择:对资料进行初审,选择脊髓研究中的与神经干细胞及神经营养因子有关的研究文献查找全文。纳入标准:①脊髓损伤中以探讨其机制及新治疗方法的文章。②探讨脊髓损伤后轴突再生,生长锥作用,引导再生方向的靶点,突触再形成及功能重建的文章。③神经营养因子和内源性神经干细胞治疗的文章。排除标准:①未被SCI收录的文章,相类似的研究。②无英文摘要的文章。资料提炼:共收集到相关文献1166篇,按上述标准纳入101篇,实际采用61篇,脊髓损伤机制相关文献12篇,轴突再生相关文献14篇,增长锥作用相关文献8篇,少突胶质细胞相关文献8篇,神经干细胞相关文献7篇,神经生长因子相关文献12篇。其余文献均被排除。资料综合:①脊髓损伤功能恢复的基础:损伤的轴突再生及增长;轴突穿透损伤瘢痕区的能力;轴突朝着正确的靶区方向再生;轴突增长到一定程度后停止,终端形成突触,与神经元相接;神经传递功能重建及运动功能重新恢复。②脊髓损伤的神经病理分析:脊髓损伤后的原发性损害、继发性损害。③脊髓损伤的分子生物学机制包括3个方面:对于成年人中枢神经系统损伤后的神经元的发展、再生,神经元通路的建立起着重要的作用轴突增长锥;对轴突的再生起到抑制作用中枢神经系统髓鞘蛋白;细胞膜和细胞内信号传递。④脊髓损伤中起重要作用的细胞和因子:少突胶质细胞,白血病抑制因子和Minocycline,内源性神经干细胞。⑤脊髓损伤动物模型:最常使用的模型是全部离断、部分离断模型和挫伤模型。⑥脊髓损伤研究的前景:已经开始把动物实验中神经营养因子和神经干细胞治疗发现用于临床,如白血病抑制因子在国外已经开始临床Ⅳ期实验,对内源性神经干细胞的诱导调控增殖研究也已经越来越受到重视。结论:神经营养因子干预治疗及神经干细胞治疗使脊髓损伤后的功能恢复成为可能。进一步探讨神经营养因子引起轴突再生的机制,将是脊髓损伤研究领域的未来方向,了解引导调控神经干细胞的增殖和分化方向,将在修复脊髓损伤方面发挥巨大的作用。 | 臧大维 刘娟 Surindar Cheema | 2007 | 中国组织工程研究与临床康复2007，11，14： | 5 |
| 3 | Brain-derived neurotrophic factors increase the proliferation and differentiation of endogenous neural stem cells in mouse models of cerebral infarction显示文摘BACKGROUND: It has been confirmed that brain-derived neurotrophic factor (BDNF) can promote the proliferation of neural stem cells (NSCs) and protect neuron-like cells in vitro. However, its effect on endogenous NSCs in vivo is still unclear. OBJECTIVE: To evaluate whether BDNF can induce the endogenous NSCs to proliferate and differentiate into the neurons in the mice model of cerebral infarction. DESIGN: A synchronal controlled observation. SETTINGS: Department of Neurology, Microbiology Division of the Department of Laboratory, Tianjin First Central Hospital; Howard Florey Institute, Medical College, the University of Melbourne. MATERIALS: Twenty-four pure breed C57BL/6J mice at the age of 10 weeks old (12 males and 12 females) were divided into saline control group and BDNF-treated group, 6 males and 6 females in each group. METHODS: The experiments were performed at the University of Melbourne from July 2004 to February 2005. ① The left middle cerebral artery (MCA) was ligated in both groups to establish models of cerebral infarction and the Matsushita measuring method was used to monitor the blood flow of the lesioned region supplied by MCA. 75% reduction of blood flow should be reached in the lesioned region. ② At 24 hours after infarction, mice in the BDNF-treated group were administrated with BDNF, which was slowly delivered using an ALZET osmium pump design. BDNF was dissolved in saline at the dosage of 500 mg/kg and injected into the pump, which could release the solution consistently in the following 28 days. The mice in the saline control group accepted the same volume of saline at 24 hours after infarction. ③ The Rotarod function test began at 1 week preoperatively, the time stayed on Rotarod was recorded. The mice were tested once a day till the end of the experiment. At 4 weeks post cerebral infarction, double labeling of Nestin and GFAP, BIII tubulin and CNPase immunostaining was performed to observe the differentiation directions of the re-expressed endogenous NSCs, and the percentages of the cells differentiated into astrocytes, neurons and oligodendrocytes were calculated. MAIN OUTCOME MEASURES: ① The differentiation directions of the re-expressed endogenous NSCs, and the percentage of the cells differentiated into astrocytes, neurons and oligodendrocytes. ② Comparison of motor function between the two groups. RESULTS: All the 24 pure C57BL/6J mice were involved in the analysis of results. ① Positively expressed endogenous NSCs appeared in the mice of both groups, and they mainly distributed around the focus of lesion, as well as the contralateral side. The expressed cells in the BDNF-treated group were obviously more than those in the saline control group. ②Activations of endogenous NSCs: At 4 weeks after infarction, re-expressions of endogenous NSCs appeared in both groups. The number of the re-expressed cells in the BDNF-treated group was about 4.2 times higher than that in the saline control group. The percentage of the cells differentiated into neurons in the BDNF-treated group was significantly higher than that in the saline control group (36%, 15%), the percentage of the cells differentiated into astrocytes was lower than that in the saline control group (54%, 77%), whereas the percentage of the cells differentiated into oligodendrocytes was similar to that in the saline control group (10%, 8%). ③ Results of motor functional test: Compared with before cerebral infarction, the mice in both groups manifested as obvious decrease in motor function at 1week after infarction, whereas the recovery of motor function in the BDNF-treated group was significantly superior to that in the saline control group at 2, 3 and 4 weeks (P < 0.01). CONCLUSION: BDNF can promote the proliferation of endogenous NSCs in the brain of mice with cerebral infarction, it can decrease the differentiation rate of astrocytes, and increase the differentiation rate of neurons. BDNF has small influence on the differentiation of endogenous NSCs into oligodendrocytes, which was not benefit for the recovery of neural axon. Endogenous NSCs may improve the motor function of mice through the above pathways. | Dawei Zang Juan Liu Xianhua Zuo Surindar Cheema | 2007 | Neural Regeneration Research2007，2，3： | 4 |
| 4 | TNFA mediates Schwann cell death by upregulating p75NTR expression without sustained activation of NFKB显示文摘 | Kristy Boyle Michael F Azari Surindar S Cheema | 2005 | Neurobiology of Disease2005，20，： | 1 |
| 5 | 突触蛋白在肌萎缩侧索硬化转基因小鼠运动神经元上的表达显示文摘目的:评估肌萎缩侧索硬化转基因小鼠脊髓前角和大脑运动皮质运动神经元上的突触蛋白在不同疾病阶段的数量变化。方法:实验于2003-11/2004-06在墨尔本大学HFI研究所脑损伤与修复组完成。表达突变人类超氧化物歧化酶1基因的转基因小鼠36只(肌萎缩侧索硬化组),以及表达B6SJL基因的正常小鼠36只(对照组),两组分别按性别及出生后60,90及120d随机分为每个时间点12只,雌雄各半。①采用荧光金标记法标记腰段脊髓及皮层的运动神经元。②采用免疫荧光方法标记突触蛋白,阳性对照为加入突触蛋白抗体并有阳性表达;阴性对照省略此抗体。③采用共焦计数系统计数并行统计学分析。结果:①荧光金标记的运动神经元:经荧光显微镜检查确定腰段脊髓及皮层的运动神经元均被荧光金清楚地标记。②运动神经元的突触蛋白计数:在疾病中期出生后90d及后期出生后120d,运动神经元上的突触蛋白的数量呈显著性降低(腰段脊髓细胞体:(0.75±0.06),(0.59±0.09)/μm;腰段脊髓树突:(0.71±0.06)(0.55±0.03)/μm;大脑皮层运动神经元细胞体:(0.79±0.03),(0.63±0.08)/μm;大脑皮层运动神经元树突:(0.76±0.07),(0.61±0.08)/μm,P<0.01);同组别雌雄对照差异无显著性。结论:肌萎缩侧索硬化运动神经元突触蛋白数量的降低与疾病及病程的进展有直接关系。 | 刘娟 臧大维 Surindar Cheema | 2006 | 中国临床康复2006，10，38： | 1 |
| 6 | Synaptophysin expression in motor neurons of transgenic mice with amyotrophic lateral sclerosis显示文摘BACKGROUND: Affected signal convection of synaptophysin on motor neurons may cause injury of motor neurons and then induce neurodegeneration and cell death in the end. OBJECTIVE: To investigate the number and density of synaptophysin on motor neurons in the anterior horn of lumbar spinal cord and sensorimotor cortex of the transgenic mouse model of amyotrophic lateral sclerosis (ALS). DESIGN: Randomized controlled animal study. SETTING: Brain Injury and Repair Group, HFI Institute of Melbourne University. MATERIALS: Transgenic mice expressing a mutated human superoxide dismutase 1 (SOD-1) were taken as ALS group (n =36), while those derived from the B6SJL-TgN gene line were taken as control group (n =36), according to the difference of gender and three postnatal time points (postnatal 60, 90 and 120 days), twelve mice of either gender were allocated in each subgroup. METHODS: The experiment was carried out in Brain Injury and Repair Group, HFI Institute of Melbourne University from November 2003 to June 2004. ① Fluorogold labeling was used for the motor neurons in the lumbar and sensorimotor cortex. ② Immunofluorescence was applied for the labeling of synaptophysin; positive control sections were represented by adding the synaptophysin antibody and the staining, showing a positive result. For negative controls, the synaptophysin antibody was omitted. ③ Stereological counting system was adopted in the statistical analysis. MAIN OUTCOME MEASURES: ① Fluorogold labeling of motor neurons; ② number of synaptophysin on the motor neurons. RESULTS: ① Fluorogold labeling of motor neurons: The motor neurons in the lumbar and sensorimotor cortex were clearly labeled by fluorogold under the detection of fluorescent microscope. ② The number of synaptophysin on the motor neurons: The number statistically decreased at the mid stage (postnatal 90 days) and late stage (postnatal 120 days) [motor neuron somas at lumbar spinal cord: (0.75±0.06), (0.59±0.09)/μm; motor neuron dendrite at lumbar spinal cord: (0.71±0.06), (0.55±0.03)/μm; motor neuron somas at sensorimotor cortex: (0.79±0.03), (0.63±0.08)/μm; motor neuron dendrite at sensorimotor cortex: (0.76±0.07), (0.61±0.08)/μm, P < 0.01]. The reduction of synaptophysin was parallel between the gender differences. CONCLUSION: Loss of synaptophysin on motor neurons is directly related to the progression of ALS. | Surindar Cheema | 2006 | Neural Regeneration Research2006，1，8： | 0 |
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