从Caveolin-1/Notch信号通路探补肾中药单体促神经干细胞增殖的作用机制
|
摘要
目的：
1.1探讨补肾中药单体淫羊藿苷和马钱苷对神经干细胞增殖的影响,明确其促神经发生的作用。
1.2从分子水平探讨补肾中药单体淫羊藿苷和马钱苷促神经干细胞增殖的作用机制,为临床使用中医药治疗脑血管病提供实验依据。
方法：
2.1建立正常与Caveolin-1敲除胎鼠脑神经干细胞体外培养体系,采用免疫细胞化学法鉴定细胞。将细胞分为空白组,淫羊藿苷不同剂量组和马钱苷不同剂量组,每组设10-6mol/L、5×10-7mol/L、10-7mol/L.5×10-8mol/L、10-8mol/L.5×10-9mol/L、10-9mol/L7个浓度,WST和神经克隆球计数的方法测定细胞增殖情况,并筛选最佳药物浓度。
2.2选用10-mol/L、5×10-7mol/L、10-7mol/L三个药物浓度作用于正常神经干细胞及Caveolin-1基因敲除小鼠神经干细胞,采用WST和神经克隆球计数的方法探讨Caveolin-1在细胞增殖中的作用。
2.3采用PCR法检测药物干预不同来源神经干细胞Notch-1、Hes-及Jagged-的表达,以进一步研究淫羊藿苷和马钱苷的作用机制。
结果：
3.1Caveolin-1敲除胎鼠神经干细胞生物特性与同源野生鼠细胞相似,但其增殖能力较强,较易出现分化。
3.2淫羊藿苷和马钱苷以剂量依赖性方式发挥促神经干细胞增殖的作用,促增殖效果随单体浓度的增高而增加。WST结果提示：除马钱苷5×10-9mol/L、109mol/L组与空白对照组相比差异无统计学意义(p>0.05),其余各组促增殖作用效果显著(p<0.05)。细胞计数结果提示：淫羊藿苷10-mol/L组和马钱苷5×10-mol/L、10-9mol/L组与空白对照组相比差异无统计学意义(p>0.05),其余各组促增殖作用效果显著(p<0.05)。
3.3Caveolin-1基因敲除细胞和正常细胞的克隆球形成差异显著(p<0.05)。淫羊藿苷和马钱苷同样以剂量依赖性方式发挥促Caveolin-1基因敲除神经干细胞增殖的作用,促增殖效果随单体浓度的增高而增加。与对照组相比,差异有统计学意义(p<0.05)。
3.4淫羊藿苷和马钱苷可以上调Notch信号通路Notch-1、Hes-1和Jagged-1的表达(p<0.05)。两种细胞比较发现,Caveolin-1基因缺失下调了Notch信号通路的表达。同一药物作用于不同细胞时,淫羊藿苷的10-6mol/L浓度组Notch-1的表达,各药物浓度组Hes-1及Jagged-1的表达差异不显著,无统计学意义(p>0.05)。马钱苷用药结果发现,马钱苷的10-6mol/L浓度组Notch-1的表达,以及10-6mol/L、5×10-7mol/L、10-7mol/L浓度组Hes-1的表达差异不显著,无统计学意义(p>0.05)。
结论：
4.1淫羊藿苷和马钱苷具有促进神经干细胞增殖的作用。
4.2Caveolin-1基因缺失影响细胞增殖。
4.3淫羊藿苷和马钱苷可通过调节Notch信号通路Notch-1、Hes-1和Jagged-1的表达以达到促神经干细胞增殖的作用。
4.4Caveolin-1影响Notch信号通路的表达
Objective:
To explore the effects of icariin and loganin on proliferation of NSC, study the molecular mechanisms of neurogenesis to provide proof for clinic.
Methods:
The NSC cultures were generated from the brain of embryonic mice. Primitive NSC were cultured, proliferated and passaged. The NSC were identified by the immunocytochemical staining of Nestin. BrdU was used to characterize the proliferation, and NF200, NSE, GFAP for the differentiation of NSC. Icariin and loganin on the proliferation of NSC were observed by the method of WST and neurospheres counting. The NSC from the brain of Caveolin-1knock-out mice were added to repeat the test of WST and neurospheres counting to investigate the mechanisms of Caveolin. The expression of Notch、 Hesl and Jagged1were detected by PCR.
Result:
The NSCs were successfully cultured and proliferated in vitro. Different dosages of Chinese Herbal Monomer could promote the proliferation of NSCs in vitro. We first investigated WST shows that except the group of loganin5×10-9mol/L、10-9mol/L (p>0.05), compared with the control group cell were increased obvious (p<0.05).The result of numbers of nerurospheres also corroborate the effect of the two Chinese Herbal Monomer could increased cell proliferation obvious (p<0.05), beside the group of icariin5×10-9mol/L and loganin5×10-mol/L and10-9mol/L (p>0.05).
When we use the NSC from the brain of Caveolin-1knock-out mice to repeat the experiment. The WST shows that every group of icariin and loganin compared with the control group cell were increased obvious (p<0.05).The result of numbers of nerurospheres also corroborate with it.
The result of PCR shows that icariin and loganin promote the proliferation of NSC in vitro significantly through up-regulated the expressions of Notch signal pathway, which the two different type of cells both manifestations the trend (p<0.05). From the comparison between the two kinds of cells were found, the deficiency of Caveolin-1could down-regulate the expressions of Notch signaling pathway between the same drug concentration group.
Conclusion:
Icariin and loganin promote the proliferation of NSC in vitro significantly through modulating Notch signal pathway expressions. Caveolin-1could regular the effect of Chinese Herbal Monomer on cell proliferation.
1.1探讨补肾中药单体淫羊藿苷和马钱苷对神经干细胞增殖的影响,明确其促神经发生的作用。
1.2从分子水平探讨补肾中药单体淫羊藿苷和马钱苷促神经干细胞增殖的作用机制,为临床使用中医药治疗脑血管病提供实验依据。
方法：
2.1建立正常与Caveolin-1敲除胎鼠脑神经干细胞体外培养体系,采用免疫细胞化学法鉴定细胞。将细胞分为空白组,淫羊藿苷不同剂量组和马钱苷不同剂量组,每组设10-6mol/L、5×10-7mol/L、10-7mol/L.5×10-8mol/L、10-8mol/L.5×10-9mol/L、10-9mol/L7个浓度,WST和神经克隆球计数的方法测定细胞增殖情况,并筛选最佳药物浓度。
2.2选用10-mol/L、5×10-7mol/L、10-7mol/L三个药物浓度作用于正常神经干细胞及Caveolin-1基因敲除小鼠神经干细胞,采用WST和神经克隆球计数的方法探讨Caveolin-1在细胞增殖中的作用。
2.3采用PCR法检测药物干预不同来源神经干细胞Notch-1、Hes-及Jagged-的表达,以进一步研究淫羊藿苷和马钱苷的作用机制。
结果：
3.1Caveolin-1敲除胎鼠神经干细胞生物特性与同源野生鼠细胞相似,但其增殖能力较强,较易出现分化。
3.2淫羊藿苷和马钱苷以剂量依赖性方式发挥促神经干细胞增殖的作用,促增殖效果随单体浓度的增高而增加。WST结果提示：除马钱苷5×10-9mol/L、109mol/L组与空白对照组相比差异无统计学意义(p>0.05),其余各组促增殖作用效果显著(p<0.05)。细胞计数结果提示：淫羊藿苷10-mol/L组和马钱苷5×10-mol/L、10-9mol/L组与空白对照组相比差异无统计学意义(p>0.05),其余各组促增殖作用效果显著(p<0.05)。
3.3Caveolin-1基因敲除细胞和正常细胞的克隆球形成差异显著(p<0.05)。淫羊藿苷和马钱苷同样以剂量依赖性方式发挥促Caveolin-1基因敲除神经干细胞增殖的作用,促增殖效果随单体浓度的增高而增加。与对照组相比,差异有统计学意义(p<0.05)。
3.4淫羊藿苷和马钱苷可以上调Notch信号通路Notch-1、Hes-1和Jagged-1的表达(p<0.05)。两种细胞比较发现,Caveolin-1基因缺失下调了Notch信号通路的表达。同一药物作用于不同细胞时,淫羊藿苷的10-6mol/L浓度组Notch-1的表达,各药物浓度组Hes-1及Jagged-1的表达差异不显著,无统计学意义(p>0.05)。马钱苷用药结果发现,马钱苷的10-6mol/L浓度组Notch-1的表达,以及10-6mol/L、5×10-7mol/L、10-7mol/L浓度组Hes-1的表达差异不显著,无统计学意义(p>0.05)。
结论：
4.1淫羊藿苷和马钱苷具有促进神经干细胞增殖的作用。
4.2Caveolin-1基因缺失影响细胞增殖。
4.3淫羊藿苷和马钱苷可通过调节Notch信号通路Notch-1、Hes-1和Jagged-1的表达以达到促神经干细胞增殖的作用。
4.4Caveolin-1影响Notch信号通路的表达
Objective:
To explore the effects of icariin and loganin on proliferation of NSC, study the molecular mechanisms of neurogenesis to provide proof for clinic.
Methods:
The NSC cultures were generated from the brain of embryonic mice. Primitive NSC were cultured, proliferated and passaged. The NSC were identified by the immunocytochemical staining of Nestin. BrdU was used to characterize the proliferation, and NF200, NSE, GFAP for the differentiation of NSC. Icariin and loganin on the proliferation of NSC were observed by the method of WST and neurospheres counting. The NSC from the brain of Caveolin-1knock-out mice were added to repeat the test of WST and neurospheres counting to investigate the mechanisms of Caveolin. The expression of Notch、 Hesl and Jagged1were detected by PCR.
Result:
The NSCs were successfully cultured and proliferated in vitro. Different dosages of Chinese Herbal Monomer could promote the proliferation of NSCs in vitro. We first investigated WST shows that except the group of loganin5×10-9mol/L、10-9mol/L (p>0.05), compared with the control group cell were increased obvious (p<0.05).The result of numbers of nerurospheres also corroborate the effect of the two Chinese Herbal Monomer could increased cell proliferation obvious (p<0.05), beside the group of icariin5×10-9mol/L and loganin5×10-mol/L and10-9mol/L (p>0.05).
When we use the NSC from the brain of Caveolin-1knock-out mice to repeat the experiment. The WST shows that every group of icariin and loganin compared with the control group cell were increased obvious (p<0.05).The result of numbers of nerurospheres also corroborate with it.
The result of PCR shows that icariin and loganin promote the proliferation of NSC in vitro significantly through up-regulated the expressions of Notch signal pathway, which the two different type of cells both manifestations the trend (p<0.05). From the comparison between the two kinds of cells were found, the deficiency of Caveolin-1could down-regulate the expressions of Notch signaling pathway between the same drug concentration group.
Conclusion:
Icariin and loganin promote the proliferation of NSC in vitro significantly through modulating Notch signal pathway expressions. Caveolin-1could regular the effect of Chinese Herbal Monomer on cell proliferation.
引文
1.全国第三次死因回顾抽样调查报告,2008,陈竺,中国协和医科大学出版社
2. Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci,1998,18 (19):7768-7778.
3. Iwai M, Sato K, Omoil N, et al. Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia[J].J Cereb Blood Flow Metab,2002,22(4):411-419.
4. Iwai M, Sato K, Kamada H, et al. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils[J]. J Cereb Blood Flow Metab, 2003,23(3):331-341.
5.甘永梅.补肾益气活血法治疗短暂性脑缺血发作临床观察.实用中医内科杂志,2011,25(11)：65-6.
6.赵清超,胡久略,黄显章.补肾醒脑方有效部位对脑缺血再灌注大鼠白细胞介素-1β和细胞间黏附分子-1表达的影响.中国实验方剂学杂志,2010,(15)；136-139.
7.周清安,李建生,王至婉等.补肾活血与益气活血方药对脑缺血老龄大鼠白介素-1和胰岛素样生长因子的影响.中国实用神经疾病杂志,2012,15(9)；28-31.
8.刘永琦,窦娟娟,吴晓晶等.补肾方药诱导BMSCs移植对脑缺血损伤NGF. BDNF、VEGF表达的影响.中成药,2011,33(4)；578-581.
9.段成竹,任国华.健脾补肾活血方对亚急性衰老大鼠慢性脑缺血模型中脑源性神经营养因子及血管内皮生长囚子表达的影响.中国老年学杂志,2012,32(4)；758-760.
10.Stichel CC, Muller HW. Experimental strategies to promote axonal regeneration after traumatic central nervous system injury. Prog Neurobiol.1998 Oct;56(2):119-48.
11.Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB. Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal, cord. Eur J Neurosci.1998 Feb;10(2):607-21.
12. Eichmann A, Le Noble F, Autiero M, Carmeliet P. Guidance of vascular and neural network formation. Curr Opin Neurobiol.2005 Feb;15 (1): 108-15.
13.Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 1992,255 (5052):1707-1710.
14.McKay R. Stem cells in the central nervous system. Science.1997 Apr4; 276(5309):66-71.
15.Massirer KB, Carromeu C, Griesi-Oliveira K, Muotri AR. Maintenance and differentiation of neural stem cells. Wiley Interdiscip Rev SystBiol Med.2011 Jan-Feb;3(1):107-14.
16.Morte MI, Carreira BP, Machado V, Carmo A, Nunes-Correia I, Carvalho CM, Araujo IM. Evaluation of proliferation of neural stem cells in vitro and in vivo. Curr Protoc Stem Cell Biol.2013 Feb;Chapter 2:Unit2D.14.
17.Willerth SM, Faxel TE, Gottlieb DI, Sakiyama-Elbert SE. The effects of soluble growth factors on embryonic stem cell differentiation inside of fibrin scaffolds. Stem Cells.2007 Sep;25(9):2235-44.
18. Wachs FP, Couillard-Despres S, Engelhardt M, Wilhelm D, Ploetz S, Vroemen M,Kaesbauer J, Uyanik G, Klucken J, Karl C, Tebbing J, Svendsen C, Weidner N, Kuhn HG, Winkler J, Aigner L. High efficacy of clonal growth and expansion of adult neural stem cells. Lab Invest.2003 Jul;83(7):949-62.
19. Cacci E, Villa A, Parmar M, Cavallaro M, Mandahl N, Lindvall 0, Martinez-Serrano A, Kokaia Z. Generation of human cortical neurons from a new immortal fetal neural stem cell line. Exp Cell Res.2007 Feb 1;313 (3):588-601.
20. Vieario-Abejon, Coll in C, Tsoulfas P, etal. Hippocampal stem cells differentiate into excitatory and inhibitory neurons,Eur J Neurosei, 2000,12:677.
21.Represa A, Shimazaki T, Simmonds M, etal.EGF— responsive neural stem cells are a transient population in the developing ousse pinal cord. Eur J Neurosei,2001,13:452 — 462.
22.Palmer TD, Ray J, Gage FH. FGF-2-responsive neuronal progenitors reside in proliferative and quieseent regions of the adult rodent brain. Mol Cell Neurosei,1995,6:474-486.
23. Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci,1998, 18(19):7768-7778.
24. Jin KL, Wang XM, Xie L. Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences of the United States of America,2006,103(35):13198-13202.
25. Song HJ, Stevens CF, Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci,2002, 5(5):438-45.
26.潘良春,尹宗生,王伟等.胚胎和新生大鼠神经干细胞培养与分化的特性比较.中国临床康复,2006,10(5)：25-27.
27.郑可.不同培养方式长期扩增神经干细胞的比较[D].大连理工大学,2005. DOI:10.7666 /d.y714823.
28.李学坤.神经干细胞的分离培养及其在老年神经退行性病中的作用研究[D].中国协和医科大学,2003.
29.赖真.淫羊藿临床活用偶拾.辽宁中医学院学报,2001,3(4)：266-266.
30.苏春芝,李静君,杜英等.益智金丹治疗老年期血管性痴呆50例疗效观察.新中医,2005,37(8)：42-44.
31.Zeng KW, Fu H, Liu GX, Wang XM. Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPK pathways [J]. Int Immunopharmacol,2010, 10(6):668-678.
32.Zhu HR, Wang ZY, Zhu XL, Wu XX, Li EG, Xu Y. Icariin protects against brain injury by enhancing SIRT1-dependent PGC-lalpha expression in experimental stroke. Neuropharmacology.2010 Jul-Aug;59(1-2):70-6.
33. Urano T, Tohda C. Icariin improves memory impairment in Alzheimer's disease model mice (5xFAD) and attenuates amyloid β-induced neurite atrophy. Phytother Res.2010 Nov;24(11):1658-63.
34.周少丞,韩晓明,王力冬等.D-半乳糖致衰老模型大鼠脑组织Ach活性、NGF表达变化及山茱萸多糖的干预作用.中国老年学杂志,2011,31(24)：4841-4842.
35.李小黎,王文,张丽等.山茱萸环烯醚帖苷对全脑缺血沙土鼠海马神经元凋亡相关因子的影响.吉林中医药,2010,30(9)：803-805.
36.李小黎,叶翠飞,张丽.山茱萸环烯醚萜苷对脑缺血沙土鼠学习记忆能力和脑内神经营养因子的影响.中华中医药学刊,2011,29(2)：263-266.
37.杨斌.淫羊藿苷药理研究概况[J].中国药房,2009,20(24)：1915-1917.
38. Sha D, Li L, Ye L, Liu R, Xu Y. Icariin inhibits neurotoxicity of beta-amyloid by upregulating cocaine-regulated and amphetamine-regulated transcripts. Neuroreport.2009 Nov 25;20(17):1564-7.
39. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS. Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol.2007 Aug;34(8):792-5.
40.李梨.淫羊藿苷对缺血再灌致脑损伤保护作用的实验研究[D].重庆医科大学,2005.
41.王晓云,王翀,黄嵘.淫羊藿苷对神经细胞缺血再灌注损害的保护作用及其机制研究[J].临床神经病学杂志,2012,25(5)：365-367.
42.钱卫庆,尹宏,孙海涛.不同浓度淫羊藿苷对大鼠成骨细胞增殖、分化的影响[J].中国医药导报,2011,8(36)：23-25.
43.卞琴,黄建华,杨铸等.三种补肾中药有效成分对皮质酮致骨质疏松大鼠骨髓间充质干细胞基因表达谱的作用.中西医结合学报,2011,9(2)：179-185.
44.谢玲玲,邹移海,刘炫斯.淫羊藿苷对骨髓间质干细胞增殖及分泌血管内皮生长因子、碱性成纤维生长因子的影响.实用医学杂志,2008,24(6)；908-910.
45.杜海斌,马华,武丽萍等.淫羊藿苷对人外周血内皮祖细胞增殖功能的影响.中国医药指南,2010,8(10)；11-13.
46.李春阳,李林,李宇航等.环烯醚萜苷对大鼠脑梗死后NF—KB与凋亡调节因子Bcl-2/Bax表达变化的影响[J].中国药理学通报,2006,22：19-22.
47.褚燕琦,李玮,李林等.山茱萸环烯醚萜苷对蛋白磷酸酶抑制剂冈田酸拟阿尔茨海默病细胞模型的作用[J].中国约理学通报,2006,22：960-963.
48.丁月霞,张丽,叶翠飞等.山茱萸环烯醚萜苷对穹隆海马伞切断大鼠海马区神经元存活和细胞凋亡调控因子的影响[J].首都医科大学学报,2011,32(1).
49. Kwon SH, Kim JA, Hong SI, Jung YH, Kim HC, Lee SY, Jang CG. Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem Int.2011 Mar;58(4):533-41.
50.王文,黄文婷,艾厚喜,李林,安易,刘茨.莫诺苷和马钱素对人神经母细胞瘤株SY5Y生长的影响[J].中国药理通讯,2007,24(2)：13-13.
51.孟庆萍,胡建鹏,王键.两种中药复方对局灶性脑缺血再灌注大鼠脑组织Hes-1、Hes-5表达的动态影响.安徽中医学院学报,2009,28(5)；52-55.
52.杜可,,曾嵘等.超微脑得健对GAP-43影响和对MCAO大鼠脑内神经再生的干预作用.湖南中医杂志,2011,27(6)：102-104.
53.,蔡光先,陈雪梅.补阳还五汤对局灶性脑缺血大鼠神经元再生的影响.中华神经医学杂志,2007,6(8)：762-765.
54.,赖鼎元,谢勇等.补阳还五汤对脑缺血大鼠经侧脑室移植神经干细胞存活和分化的影响.中国中西医结合急救杂志,2009,16(1)；22-25.
55.易健,黄昕,谢勇.脑得健方对大鼠局灶性脑缺血后神经功能及梗死面积的影响.湖南中医药大学学报,2010,(1)：9-11.
56. Shaul PW, Anderson RG. Role of plasmalemmalcaveolae in signal transduction. Am J Physiol.1998,275:843 851.
57.Glenney JR Jr, Soppet D. Sequence and expression of caveolin, a protein component of caveolae plasma membrane domains phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts. ProcNatlAcadSci U S A.1992;89 (21):10517-21.
58. Razani B, Woodman SE, Lisanti MP. Caveolae:from cell biology to animal physiology. Pharmacological reviews.2002,54:431-467.
59. Trushina E, Du Charme J, Parisi J, McMurray CT. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res.2006 Sep 15;172(1):24-32.
60.,易健,蔡光先,Caveolin-1敲除对C57BL/6小鼠繁殖性能及子代离乳前体质量的影响[J].湖南中医药大学学报,2011,(11).
61. Oka N, Yamamoto M, Schwencke C. Caveolin interaction with protein kinase C. Isoenzyme—dependent regulation of kinase activity by the caveolin scaffolding domain peptide [J]. BiolChem,1997,272:33416-33421.
62.Schubert W, Sotgia F, Cohen AW, et al. Caveolin-1(-/-)-and caveolin-2(-/-)-deficient mice both display numerous skeletal muscle abnormalities, with tubular aggregate formation.Am J Pathol.2007 Jan;170.:316-33.
63.Alex W. Cohen, David S. Park, Scott E. Woodman, Terrence M. Williams, et al. Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiacfibroblasts. Am J Physiol Cell Physiol.2003; 284:C457-C474.
64.Medina FA, Cohen AW, de Almeida CJ,etal. Immune dysfunction in caveolin-1 null mice following infection with Trypanosomacruzi (Tulahuen strain). Microbes Infect.2007;9.:325-33.
65.Park DS, Lee H, Frank PG, et al. Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. MolBiol Cell. 2002;13.:3416-30.
66.Nixon SJ, Carter A, Wegner J. Ferguson C, et al. Caveolin-1 is required for lateral line neuromast and notochord development. J Cell Sci.2007;120:2151-61.
67.连永亮,邹萍,马依妮等.小鼠皮层caveolin-1蛋白表达与作业成绩的相关性[J].中华行为医学与脑科学杂志,2011,20(10)：872-874.
68.邹伟,王红霞,刘晶等.大鼠脑内caveolin-1蛋白的表达及其在分辨学习中的作用[J].生理学报,2006,58(5)：429-434.
69. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, Bonds JA, Schilling JM, Miyanohara A, Headrick J, Ali SS, Roth DM, Patel PM, Patel HH. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One.2010 Dec 23;5 (12):e15697.
70.Jasmin JF, Malhotra S, Singh Dhallu M, Mercier I, Rosenbaum DM, Lisanti MP. Caveolin-1 deficiency increases cerebral ischemic injury. Circ Res.2007 Mar 16; 100(5):721-9.
71. Gu Y, Zheng G, Xu M, Li Y, Chen X, Zhu W, Tong Y, Chung SK, Liu KJ, Shen J. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem.2012 Jan;120(1):147-56.
72.Head BP, Patel HH, Tsutsumi YM, Hu Y, Mejia T, Mora RC, Insel PA, Roth DM, Drummond JC, Patel PM:Caveolin-1 expression is essential for N-methyl-D-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death. FASEB J 2008,22:828-840.
73.,易健,刘富林.局灶性脑缺血对caveolin-1敲除小鼠细胞增殖与神经胶质纤维酸性蛋白表达的影响[J].中华行为医学与脑科学杂志,2012,21(3)：216-218.
74. Chang CF, Chen SF, Lee TS, Lee HF, Chen SF, Shyue SK. Caveolin-1 deletion reduces early brain injury after experimental intracerebral hemorrhage. Am J Pathol.2011 Apr;178(4):1749-61.
75. Jasmin JF, Yang M, Tacovitti L, Lisanti MP. Genetic ablation of caveolin-1 increases neural stem cell proliferation in the subventricular zone (SVZ) of the adult mouse brain. Cell Cycle.2009 Dec;8(23):3978-83.)
76. Li Y, Luo J, Lau WM, Zheng G, Fu S, Wang TT, Zeng HP, So KF, Chung SK, Tong Y, Liu K, Shen J. Caveolin-1 plays a crucial role in inhibiting neuronal differentiation of neural stem/progenitor cells via VEGF signaling-dependent pathway. PLoS One.2011:6(8):e22901.
77. Li Y, Lau WM, So KF, Tong Y, Shen J. Caveolin-1 promote astroglial differen tiation of neural stem/progenitor cells through modulating Notchl/NICD and Hesl expressions. Biochem Biophys Res Commun.2011 Apr 15:407(3):517-24.
78. Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D, Yeo SY, Lorick K, Wright GJ, Ariza-McNaughton L, Weissman AM, Lewis J, Chandrasekharappa SC, Chitnis AB. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell.2003 Jan;4(1):67-82.
79. Black IB, Woodbury D. Adult rat and human bone marrow stromal stem cells differentiate into neurons. Blood cells Mol Dis,2001,27 (3):632—636.
80. Lo L, Dormand E, Greenwood A, Anderson DJ. Comparison of the generic neuronal differentiation and neuron subtype specification functions of mammalian achaete-scute and atonal homologs in cultured neural progenitor cells. Development.2002 Apr;129(7):1553-67.
81.Okano H, Imai T, Okabe M. Musashi:a translational regulator of cell fate. J Cell Sci,2002,115 (Pt7):1355—1359.
82.Artavanis Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science.1999 Apr 30;284(5415):770-6.
83. Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, Temple S. Timing of CNS cell generation:A programmed sequence of neuron and glia cell production from isolated murine cortical stem cells. Neuron.2000:28:69-80.
84. Gaiano N, Nye JS, Fishell G. Radial glial identity is promoted by Notchl signaling in the murine forebrain. Neuron.2000:26:395-404.
85. Okano H, Imai T, Okabe M. Musashi:a translational regulator of cell fate. J Cell Sci,2002,115 (Pt7):1355—1359.
86.Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev.2002 Apr 1; 16(7):846-58.
87. Kageyama R Ishibashi M, Takebayashi K et al. bHLH transcription factors and mammalign neuronal di erentiation. Int JBiochem Cell Bioh.1997,29(12): 1389—1399.
88. Ishibashi M, Ang SL, Shiota K, et al. Targeted disruption of mammalian hairy and Enhancer of split homolog—(HES-1) leads to up-regulation of neural helix-loop-helixfactors premature neurogenesi, and severe neural tube defects. Genes Dev.1995,9(24):3136-3148.
89. John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF. Multiple sclerosis:re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med.2002 Oct;8(10):1115-21.
90. Nyfeler Y, Kirch RD, Mantei N, Leone DP, Radtke F, Suter U, Taylor V. Jaggedl signals in the postnatal subventricular zone are required for neural stem cell self-renewal. EMBO J.2005 Oct;24(19):3504-15.
91.樊拥军,崔筱英.Jaggedl蛋白抑制神经干细胞向神经元分化的实验.中国生物学文摘,2006,20(6)：26-26.
92.Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA. Notch receptor activation inhibits oligodendrocyte different-iation. Neuron.1998 Jul;21(1):63-75.
93.吕威力,邢雪松.脑缺血再灌注海马齿状回神经干细胞Mash-1的表达.中国组织工程研究与临床康复,2011,15(45)：8451-8454.
94.朱晓峰,戚句中,时晶等.远志总皂苷对海马神经干细胞定向分化的作用及对Mashl表达的影响.中华神经医学杂志,2009,(12)；1193-1196.
95. Ball DW. Achaete-scute homolog—1 and Notch in lung neurondocrine developm-ent and cancer. Cancer Lett.2004,204:159—169.
96.Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell.1993 Nov 5; 75 (3):463-76.
97. Nieto M, Schuurmans C, Britz 0, Guillemot F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron.2001 Feb;29(2):401-13.
98. Nagaoka T, Karasawa H, Castro NP, Rangel MC, Salomon DS, Bianco C. An evolving web of signaling networks regulated by Cripto-1. Growth Factors. 2012 Feb;30(1):13-21.
99.Campos LS, Decker L, Taylor V, Skarnes W. Notch, epidermal growth factor receptor, and betal-integrin pathways are coordinated in neural stem cells. J Biol Chem.2006 Feb 24;281 (8):5300-9.
100.Xu K, Usary J, Kousis PC, Prat A, Wang DY, Adams JR, Wang W, Loch AJ, Deng T, Zhao W, Cardiff RD, Yoon K, Gaiano N, Ling V, Beyene J, Zacksenhaus E, Gridley T, Leong WL, Guidos CJ, Perou CM, Egan SE. Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell.2012 May 15;21(5):626-41.
101.Wang S, Kan Q, Sun Y, Han R, Zhang G, Peng T, Jia Y. Caveolin-1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling. Int J Dev Neurosci.2013 Feb;31(1):30-5.
1. McKay R. Stem cells in the central nervous system. Science.1997 Apr4;276(5309):66-71.Massirer KB, Carromeu C, Griesi-Oliveira K, Muotri AR. Maintenance and differentiation of neural stem cells. Wiley Interdiscip Rev SystBiol Med.2011 Jan-Feb;3(1):107-14.
2.王畅,张艳军,冯英等.淫羊藿苷对短暂性前脑缺血模型大鼠海马神经再生的影响.中草药,2009,(5)：754-758
3.许亮.淫羊藿营对大鼠脑缺血再灌注后神经元的保护作用.临床神经病学杂志,2011,24(3)：198-201
4.柴丽娟,钟佩茹,周志焕.淫羊藿苷对体外神经干细胞增殖作用影响的研究.中国药理学通报,2010,26(5)：670-673
5.杨斌.淫羊覆苷药理研究概况[J].中国药房,2009,20(24)：1915-1917.
6. Sha D, Li L, Ye L, Liu R, Xu Y. Icariin inhibits neurotoxicity of beta-amyloid by upregulating cocaine-regulated and amphetamine-regulated transcripts. Neuroreport.2009 Nov 25;20 (17):1564-7.
7. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS. Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol.2007 Aug;34(8):792-5.
8.李梨.淫羊藿苷对缺血再灌致脑损伤保护作用的实验研究[D].重庆医科大学,2005.
9. Zeng KW, Fu H, Liu GX, Wang XM. Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPK pathways[J]. Int Immunopharmacol,2010,10(6):668-678.
10.王晓云,王翀,黄嵘.淫羊藿苷对神经细胞缺血再灌注损害的保护作用及其机制研究[J].临床神经病学杂志,2012,25(5)：365-367.
11.魏海珍.齐墩果酸对损伤血管内皮细胞的保护作用及其机制探讨.南京医科大学学报：自然科学版,2012,32(11)：1505-1510
12.赵坚华,韩春姬.轮叶党参中的齐墩果酸对紫外线照射所诱发DNA损伤的保护作用.延边大学医学学报,2012,35(1)：22-24
13.汤华成,张东杰,赵蕾.功能性食品因子齐墩果酸研究进展.食品科技,2007,32(9)；16-18陈志辉,徐良梅,李建平.齐墩果酸研究进展.饲料博览,2010,(6)；7-9
14.张玉莲,刘爽.补肾中药有效成分对SAMP8小鼠海马APP及PS1基因表达的影响[J].天津中医药,2012,29(1)：59-61.
15.李春阳,李林,李宇航等.环烯醚萜苷对大鼠脑梗死后NF—KB与凋亡调节因子Bcl-2/Bax表达变化的影响[J].中国药理学通报,2006,22：19-22.
16.褚燕琦,李玮,李林等.山茱萸环烯醚萜苷对蛋白磷酸酶抑制剂冈田酸拟阿尔茨海默病细胞模型的作用[J].中国约理学通报,2006,22：960--963.
17.丁月霞,张丽,叶翠飞等.山茱萸环烯醚萜苷对穹隆海马伞切断大鼠海马区神经元存活和细胞凋亡调控因子的影响[J].首都医科大学学报,2011,32(1).
18.李小黎,王文,张丽等.山茱萸环烯醚帖苷对全脑缺血沙土鼠海马神经元凋亡相关因子的影响[J].吉林中医药,2010,30(9)
19. Kwon SH, Kim JA, Hong SI, Jung YH, Kim HC, Lee SY, Jang CG. Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK,p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem Int.2011 Mar;58(4):533-41.
20.王文,黄文婷,艾厚喜,李林,安易,刘茨.莫诺苷和马钱素对人神经母细胞瘤株SY5Y生长的影响[J].中国药理通讯,2007,24(2)：13-13.
21.张永强,程岗,章薇等.白藜芦醇对缺血再灌注小鼠神经干细胞增殖作用的研究[J].中华神经外科疾病研究杂志,2010,9(6)：484-487.
22.陈岩,李志伟,杨谦.丹参酮对大鼠脑缺血后神经干细胞增殖影响的研究[J].陕西医学杂志,2011,40(7)：774-775.
23.赵雪花.葛根素对大鼠脑缺血再灌注后Caspase-3和c-fos表达的影响[J].数理医药学杂志,2012,25(5)：511-512.
24.李志伟,穆英,郭荷娜等.葛根素对短暂性前脑缺血大鼠学习能力及神经干细胞增殖的影响[J].陕西医学杂志,2012,(11)：1454-1454.
25.杨谦,李志伟,穆英等.葛根素对去卵巢雌性大鼠脑内BDNF表达和神经干细胞增殖的影响[J].陕西医学杂志,2012,(7)：778-779.
26.张建平,司银楚.人参皂菅Rgl对成年大鼠脑缺血海马区神经干细胞的影响[J].第四军医大学学报,2008,29(24)：2225-2228.
27.崔荣太,蒲传强.人参皂甙Rgl对大鼠局灶性脑缺血后侧脑室下区神经干细胞增殖分化的影响[J].中华老年心脑血管病杂志,2007,9(10)：707-709.
28.崔荣太,蒲传强.人参皂甙Rgl对大鼠局灶性脑缺血脑组织神经干细胞增殖的影响[J].解放军医学杂志,2007,32(8)：842-845.
29.崔荣太,蒲传强.人参皂甙Rgl对体外培养大鼠神经干细胞的增殖作用[J].军医进修学院学报,2008,29(1)：22-22.
30.周志焕,王秀云,钟佩茹等.人参皂苷Rgl对体外培养胚胎神经干细胞增殖作用的影响[J].中国中医药信息杂志,2010,(2)：28-30.
31.庄朋伟,张艳军,庞坦.人参皂苷Rgl促进体外培养神经干细胞增殖的研究[J].中国中药杂j志,2009,(4)：443-446.
32.司银楚,李巾伟,张丽娟.三七总皂苷促进脑出血后侧脑室室管膜下神经干细胞的增殖和分化[J].中国组织工程研究与临床康复,2008,12(8)：1414-1417.
33.司银楚,成龙,洪庆涛等.三七总皂甙促进离体胎鼠皮层神经干细胞增殖、分化的实验研究[J].中国体视学与图像分析,2004,9(2)：78-83.
34.张建平,司银楚,朱培纯.三七总皂苷对体外培养的大鼠海马神经干细胞增殖分化的作用[J].解剖学报,2010,(3)：362-366.
35.王济潍,陈文,王玉良.EGb761对血管性痴呆大鼠海马齿状回神经干细胞增殖分化的影响[J].神经解剖学杂志,2012,28(6)：589-594.
36.李蕊,袁宝强,樊秋萍.银杏叶提取物对发育期戊四氮点燃癫痫大鼠学习记忆与海马神经干细胞增殖、分化的影响[J].实用儿科临床杂志,2011,26(23)：1821-1824.
37.张红梅,张琳,关涛.银杏叶提取物促进帕金森病模型小鼠窒管膜下区神经干细胞增殖作用的研究[J].世界中西医结合杂志,2008,3(9)：518-520.
38.张皓楠,王益民.银杏叶提取物对胎鼠皮质神经元细胞的影响[J].天津中医药大学学报,2012,31(4)：218-220.
39.李晓涛,路来金.银杏叶提取物对大鼠神经干细胞分化为神经元样细胞的影响[J].中国老年学杂志,2010,30(14)：2002-2003.
40.高诗豪,唐政恒,陈图南.蜕皮甾酮对大鼠脑组织自由基损伤的保护作用[J].第三军医大学学报,2012,34(23)：2357-2359.
41.陈月,李晓赫,陈福军等.β-蜕皮甾酮对匹罗卡品致痫小鼠海马神经元凋亡相关基因表达的影响[J].解剖科学进展,2012,18(1)：66-69
42.陈月,孟令慧,冯婉玉.β-蜕皮甾酮对APP/PS-1转基因小鼠学习记忆能力及海马Bel-2、 Bax蛋白表达的影响[J].解剖科学进展,2011,17(5)：440-444.
43.罗春霞,张映琦,迟路湘等.蜕皮甾酮对大鼠局灶性脑梗死的保护作用及机制初讨[J].西南国防医药,2009,19(2)：176-178.
44.储卫华,詹梦熊,朱刚等.EDS对新生SD大鼠海马神经干细胞增殖分化的作用[J].第三军医大学学报,2008,30(19)：1787-1790.
2. Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci,1998,18 (19):7768-7778.
3. Iwai M, Sato K, Omoil N, et al. Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia[J].J Cereb Blood Flow Metab,2002,22(4):411-419.
4. Iwai M, Sato K, Kamada H, et al. Temporal profile of stem cell division, migration, and differentiation from subventricular zone to olfactory bulb after transient forebrain ischemia in gerbils[J]. J Cereb Blood Flow Metab, 2003,23(3):331-341.
5.甘永梅.补肾益气活血法治疗短暂性脑缺血发作临床观察.实用中医内科杂志,2011,25(11)：65-6.
6.赵清超,胡久略,黄显章.补肾醒脑方有效部位对脑缺血再灌注大鼠白细胞介素-1β和细胞间黏附分子-1表达的影响.中国实验方剂学杂志,2010,(15)；136-139.
7.周清安,李建生,王至婉等.补肾活血与益气活血方药对脑缺血老龄大鼠白介素-1和胰岛素样生长因子的影响.中国实用神经疾病杂志,2012,15(9)；28-31.
8.刘永琦,窦娟娟,吴晓晶等.补肾方药诱导BMSCs移植对脑缺血损伤NGF. BDNF、VEGF表达的影响.中成药,2011,33(4)；578-581.
9.段成竹,任国华.健脾补肾活血方对亚急性衰老大鼠慢性脑缺血模型中脑源性神经营养因子及血管内皮生长囚子表达的影响.中国老年学杂志,2012,32(4)；758-760.
10.Stichel CC, Muller HW. Experimental strategies to promote axonal regeneration after traumatic central nervous system injury. Prog Neurobiol.1998 Oct;56(2):119-48.
11.Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB. Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal, cord. Eur J Neurosci.1998 Feb;10(2):607-21.
12. Eichmann A, Le Noble F, Autiero M, Carmeliet P. Guidance of vascular and neural network formation. Curr Opin Neurobiol.2005 Feb;15 (1): 108-15.
13.Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 1992,255 (5052):1707-1710.
14.McKay R. Stem cells in the central nervous system. Science.1997 Apr4; 276(5309):66-71.
15.Massirer KB, Carromeu C, Griesi-Oliveira K, Muotri AR. Maintenance and differentiation of neural stem cells. Wiley Interdiscip Rev SystBiol Med.2011 Jan-Feb;3(1):107-14.
16.Morte MI, Carreira BP, Machado V, Carmo A, Nunes-Correia I, Carvalho CM, Araujo IM. Evaluation of proliferation of neural stem cells in vitro and in vivo. Curr Protoc Stem Cell Biol.2013 Feb;Chapter 2:Unit2D.14.
17.Willerth SM, Faxel TE, Gottlieb DI, Sakiyama-Elbert SE. The effects of soluble growth factors on embryonic stem cell differentiation inside of fibrin scaffolds. Stem Cells.2007 Sep;25(9):2235-44.
18. Wachs FP, Couillard-Despres S, Engelhardt M, Wilhelm D, Ploetz S, Vroemen M,Kaesbauer J, Uyanik G, Klucken J, Karl C, Tebbing J, Svendsen C, Weidner N, Kuhn HG, Winkler J, Aigner L. High efficacy of clonal growth and expansion of adult neural stem cells. Lab Invest.2003 Jul;83(7):949-62.
19. Cacci E, Villa A, Parmar M, Cavallaro M, Mandahl N, Lindvall 0, Martinez-Serrano A, Kokaia Z. Generation of human cortical neurons from a new immortal fetal neural stem cell line. Exp Cell Res.2007 Feb 1;313 (3):588-601.
20. Vieario-Abejon, Coll in C, Tsoulfas P, etal. Hippocampal stem cells differentiate into excitatory and inhibitory neurons,Eur J Neurosei, 2000,12:677.
21.Represa A, Shimazaki T, Simmonds M, etal.EGF— responsive neural stem cells are a transient population in the developing ousse pinal cord. Eur J Neurosei,2001,13:452 — 462.
22.Palmer TD, Ray J, Gage FH. FGF-2-responsive neuronal progenitors reside in proliferative and quieseent regions of the adult rodent brain. Mol Cell Neurosei,1995,6:474-486.
23. Liu J, Solway K, Messing RO, et al. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci,1998, 18(19):7768-7778.
24. Jin KL, Wang XM, Xie L. Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences of the United States of America,2006,103(35):13198-13202.
25. Song HJ, Stevens CF, Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci,2002, 5(5):438-45.
26.潘良春,尹宗生,王伟等.胚胎和新生大鼠神经干细胞培养与分化的特性比较.中国临床康复,2006,10(5)：25-27.
27.郑可.不同培养方式长期扩增神经干细胞的比较[D].大连理工大学,2005. DOI:10.7666 /d.y714823.
28.李学坤.神经干细胞的分离培养及其在老年神经退行性病中的作用研究[D].中国协和医科大学,2003.
29.赖真.淫羊藿临床活用偶拾.辽宁中医学院学报,2001,3(4)：266-266.
30.苏春芝,李静君,杜英等.益智金丹治疗老年期血管性痴呆50例疗效观察.新中医,2005,37(8)：42-44.
31.Zeng KW, Fu H, Liu GX, Wang XM. Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPK pathways [J]. Int Immunopharmacol,2010, 10(6):668-678.
32.Zhu HR, Wang ZY, Zhu XL, Wu XX, Li EG, Xu Y. Icariin protects against brain injury by enhancing SIRT1-dependent PGC-lalpha expression in experimental stroke. Neuropharmacology.2010 Jul-Aug;59(1-2):70-6.
33. Urano T, Tohda C. Icariin improves memory impairment in Alzheimer's disease model mice (5xFAD) and attenuates amyloid β-induced neurite atrophy. Phytother Res.2010 Nov;24(11):1658-63.
34.周少丞,韩晓明,王力冬等.D-半乳糖致衰老模型大鼠脑组织Ach活性、NGF表达变化及山茱萸多糖的干预作用.中国老年学杂志,2011,31(24)：4841-4842.
35.李小黎,王文,张丽等.山茱萸环烯醚帖苷对全脑缺血沙土鼠海马神经元凋亡相关因子的影响.吉林中医药,2010,30(9)：803-805.
36.李小黎,叶翠飞,张丽.山茱萸环烯醚萜苷对脑缺血沙土鼠学习记忆能力和脑内神经营养因子的影响.中华中医药学刊,2011,29(2)：263-266.
37.杨斌.淫羊藿苷药理研究概况[J].中国药房,2009,20(24)：1915-1917.
38. Sha D, Li L, Ye L, Liu R, Xu Y. Icariin inhibits neurotoxicity of beta-amyloid by upregulating cocaine-regulated and amphetamine-regulated transcripts. Neuroreport.2009 Nov 25;20(17):1564-7.
39. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS. Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol.2007 Aug;34(8):792-5.
40.李梨.淫羊藿苷对缺血再灌致脑损伤保护作用的实验研究[D].重庆医科大学,2005.
41.王晓云,王翀,黄嵘.淫羊藿苷对神经细胞缺血再灌注损害的保护作用及其机制研究[J].临床神经病学杂志,2012,25(5)：365-367.
42.钱卫庆,尹宏,孙海涛.不同浓度淫羊藿苷对大鼠成骨细胞增殖、分化的影响[J].中国医药导报,2011,8(36)：23-25.
43.卞琴,黄建华,杨铸等.三种补肾中药有效成分对皮质酮致骨质疏松大鼠骨髓间充质干细胞基因表达谱的作用.中西医结合学报,2011,9(2)：179-185.
44.谢玲玲,邹移海,刘炫斯.淫羊藿苷对骨髓间质干细胞增殖及分泌血管内皮生长因子、碱性成纤维生长因子的影响.实用医学杂志,2008,24(6)；908-910.
45.杜海斌,马华,武丽萍等.淫羊藿苷对人外周血内皮祖细胞增殖功能的影响.中国医药指南,2010,8(10)；11-13.
46.李春阳,李林,李宇航等.环烯醚萜苷对大鼠脑梗死后NF—KB与凋亡调节因子Bcl-2/Bax表达变化的影响[J].中国药理学通报,2006,22：19-22.
47.褚燕琦,李玮,李林等.山茱萸环烯醚萜苷对蛋白磷酸酶抑制剂冈田酸拟阿尔茨海默病细胞模型的作用[J].中国约理学通报,2006,22：960-963.
48.丁月霞,张丽,叶翠飞等.山茱萸环烯醚萜苷对穹隆海马伞切断大鼠海马区神经元存活和细胞凋亡调控因子的影响[J].首都医科大学学报,2011,32(1).
49. Kwon SH, Kim JA, Hong SI, Jung YH, Kim HC, Lee SY, Jang CG. Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem Int.2011 Mar;58(4):533-41.
50.王文,黄文婷,艾厚喜,李林,安易,刘茨.莫诺苷和马钱素对人神经母细胞瘤株SY5Y生长的影响[J].中国药理通讯,2007,24(2)：13-13.
51.孟庆萍,胡建鹏,王键.两种中药复方对局灶性脑缺血再灌注大鼠脑组织Hes-1、Hes-5表达的动态影响.安徽中医学院学报,2009,28(5)；52-55.
52.杜可,,曾嵘等.超微脑得健对GAP-43影响和对MCAO大鼠脑内神经再生的干预作用.湖南中医杂志,2011,27(6)：102-104.
53.,蔡光先,陈雪梅.补阳还五汤对局灶性脑缺血大鼠神经元再生的影响.中华神经医学杂志,2007,6(8)：762-765.
54.,赖鼎元,谢勇等.补阳还五汤对脑缺血大鼠经侧脑室移植神经干细胞存活和分化的影响.中国中西医结合急救杂志,2009,16(1)；22-25.
55.易健,黄昕,谢勇.脑得健方对大鼠局灶性脑缺血后神经功能及梗死面积的影响.湖南中医药大学学报,2010,(1)：9-11.
56. Shaul PW, Anderson RG. Role of plasmalemmalcaveolae in signal transduction. Am J Physiol.1998,275:843 851.
57.Glenney JR Jr, Soppet D. Sequence and expression of caveolin, a protein component of caveolae plasma membrane domains phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts. ProcNatlAcadSci U S A.1992;89 (21):10517-21.
58. Razani B, Woodman SE, Lisanti MP. Caveolae:from cell biology to animal physiology. Pharmacological reviews.2002,54:431-467.
59. Trushina E, Du Charme J, Parisi J, McMurray CT. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res.2006 Sep 15;172(1):24-32.
60.,易健,蔡光先,Caveolin-1敲除对C57BL/6小鼠繁殖性能及子代离乳前体质量的影响[J].湖南中医药大学学报,2011,(11).
61. Oka N, Yamamoto M, Schwencke C. Caveolin interaction with protein kinase C. Isoenzyme—dependent regulation of kinase activity by the caveolin scaffolding domain peptide [J]. BiolChem,1997,272:33416-33421.
62.Schubert W, Sotgia F, Cohen AW, et al. Caveolin-1(-/-)-and caveolin-2(-/-)-deficient mice both display numerous skeletal muscle abnormalities, with tubular aggregate formation.Am J Pathol.2007 Jan;170.:316-33.
63.Alex W. Cohen, David S. Park, Scott E. Woodman, Terrence M. Williams, et al. Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiacfibroblasts. Am J Physiol Cell Physiol.2003; 284:C457-C474.
64.Medina FA, Cohen AW, de Almeida CJ,etal. Immune dysfunction in caveolin-1 null mice following infection with Trypanosomacruzi (Tulahuen strain). Microbes Infect.2007;9.:325-33.
65.Park DS, Lee H, Frank PG, et al. Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. MolBiol Cell. 2002;13.:3416-30.
66.Nixon SJ, Carter A, Wegner J. Ferguson C, et al. Caveolin-1 is required for lateral line neuromast and notochord development. J Cell Sci.2007;120:2151-61.
67.连永亮,邹萍,马依妮等.小鼠皮层caveolin-1蛋白表达与作业成绩的相关性[J].中华行为医学与脑科学杂志,2011,20(10)：872-874.
68.邹伟,王红霞,刘晶等.大鼠脑内caveolin-1蛋白的表达及其在分辨学习中的作用[J].生理学报,2006,58(5)：429-434.
69. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, Bonds JA, Schilling JM, Miyanohara A, Headrick J, Ali SS, Roth DM, Patel PM, Patel HH. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One.2010 Dec 23;5 (12):e15697.
70.Jasmin JF, Malhotra S, Singh Dhallu M, Mercier I, Rosenbaum DM, Lisanti MP. Caveolin-1 deficiency increases cerebral ischemic injury. Circ Res.2007 Mar 16; 100(5):721-9.
71. Gu Y, Zheng G, Xu M, Li Y, Chen X, Zhu W, Tong Y, Chung SK, Liu KJ, Shen J. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood-brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem.2012 Jan;120(1):147-56.
72.Head BP, Patel HH, Tsutsumi YM, Hu Y, Mejia T, Mora RC, Insel PA, Roth DM, Drummond JC, Patel PM:Caveolin-1 expression is essential for N-methyl-D-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death. FASEB J 2008,22:828-840.
73.,易健,刘富林.局灶性脑缺血对caveolin-1敲除小鼠细胞增殖与神经胶质纤维酸性蛋白表达的影响[J].中华行为医学与脑科学杂志,2012,21(3)：216-218.
74. Chang CF, Chen SF, Lee TS, Lee HF, Chen SF, Shyue SK. Caveolin-1 deletion reduces early brain injury after experimental intracerebral hemorrhage. Am J Pathol.2011 Apr;178(4):1749-61.
75. Jasmin JF, Yang M, Tacovitti L, Lisanti MP. Genetic ablation of caveolin-1 increases neural stem cell proliferation in the subventricular zone (SVZ) of the adult mouse brain. Cell Cycle.2009 Dec;8(23):3978-83.)
76. Li Y, Luo J, Lau WM, Zheng G, Fu S, Wang TT, Zeng HP, So KF, Chung SK, Tong Y, Liu K, Shen J. Caveolin-1 plays a crucial role in inhibiting neuronal differentiation of neural stem/progenitor cells via VEGF signaling-dependent pathway. PLoS One.2011:6(8):e22901.
77. Li Y, Lau WM, So KF, Tong Y, Shen J. Caveolin-1 promote astroglial differen tiation of neural stem/progenitor cells through modulating Notchl/NICD and Hesl expressions. Biochem Biophys Res Commun.2011 Apr 15:407(3):517-24.
78. Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D, Yeo SY, Lorick K, Wright GJ, Ariza-McNaughton L, Weissman AM, Lewis J, Chandrasekharappa SC, Chitnis AB. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell.2003 Jan;4(1):67-82.
79. Black IB, Woodbury D. Adult rat and human bone marrow stromal stem cells differentiate into neurons. Blood cells Mol Dis,2001,27 (3):632—636.
80. Lo L, Dormand E, Greenwood A, Anderson DJ. Comparison of the generic neuronal differentiation and neuron subtype specification functions of mammalian achaete-scute and atonal homologs in cultured neural progenitor cells. Development.2002 Apr;129(7):1553-67.
81.Okano H, Imai T, Okabe M. Musashi:a translational regulator of cell fate. J Cell Sci,2002,115 (Pt7):1355—1359.
82.Artavanis Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science.1999 Apr 30;284(5415):770-6.
83. Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, Temple S. Timing of CNS cell generation:A programmed sequence of neuron and glia cell production from isolated murine cortical stem cells. Neuron.2000:28:69-80.
84. Gaiano N, Nye JS, Fishell G. Radial glial identity is promoted by Notchl signaling in the murine forebrain. Neuron.2000:26:395-404.
85. Okano H, Imai T, Okabe M. Musashi:a translational regulator of cell fate. J Cell Sci,2002,115 (Pt7):1355—1359.
86.Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev.2002 Apr 1; 16(7):846-58.
87. Kageyama R Ishibashi M, Takebayashi K et al. bHLH transcription factors and mammalign neuronal di erentiation. Int JBiochem Cell Bioh.1997,29(12): 1389—1399.
88. Ishibashi M, Ang SL, Shiota K, et al. Targeted disruption of mammalian hairy and Enhancer of split homolog—(HES-1) leads to up-regulation of neural helix-loop-helixfactors premature neurogenesi, and severe neural tube defects. Genes Dev.1995,9(24):3136-3148.
89. John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF. Multiple sclerosis:re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med.2002 Oct;8(10):1115-21.
90. Nyfeler Y, Kirch RD, Mantei N, Leone DP, Radtke F, Suter U, Taylor V. Jaggedl signals in the postnatal subventricular zone are required for neural stem cell self-renewal. EMBO J.2005 Oct;24(19):3504-15.
91.樊拥军,崔筱英.Jaggedl蛋白抑制神经干细胞向神经元分化的实验.中国生物学文摘,2006,20(6)：26-26.
92.Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA. Notch receptor activation inhibits oligodendrocyte different-iation. Neuron.1998 Jul;21(1):63-75.
93.吕威力,邢雪松.脑缺血再灌注海马齿状回神经干细胞Mash-1的表达.中国组织工程研究与临床康复,2011,15(45)：8451-8454.
94.朱晓峰,戚句中,时晶等.远志总皂苷对海马神经干细胞定向分化的作用及对Mashl表达的影响.中华神经医学杂志,2009,(12)；1193-1196.
95. Ball DW. Achaete-scute homolog—1 and Notch in lung neurondocrine developm-ent and cancer. Cancer Lett.2004,204:159—169.
96.Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell.1993 Nov 5; 75 (3):463-76.
97. Nieto M, Schuurmans C, Britz 0, Guillemot F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron.2001 Feb;29(2):401-13.
98. Nagaoka T, Karasawa H, Castro NP, Rangel MC, Salomon DS, Bianco C. An evolving web of signaling networks regulated by Cripto-1. Growth Factors. 2012 Feb;30(1):13-21.
99.Campos LS, Decker L, Taylor V, Skarnes W. Notch, epidermal growth factor receptor, and betal-integrin pathways are coordinated in neural stem cells. J Biol Chem.2006 Feb 24;281 (8):5300-9.
100.Xu K, Usary J, Kousis PC, Prat A, Wang DY, Adams JR, Wang W, Loch AJ, Deng T, Zhao W, Cardiff RD, Yoon K, Gaiano N, Ling V, Beyene J, Zacksenhaus E, Gridley T, Leong WL, Guidos CJ, Perou CM, Egan SE. Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell.2012 May 15;21(5):626-41.
101.Wang S, Kan Q, Sun Y, Han R, Zhang G, Peng T, Jia Y. Caveolin-1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling. Int J Dev Neurosci.2013 Feb;31(1):30-5.
1. McKay R. Stem cells in the central nervous system. Science.1997 Apr4;276(5309):66-71.Massirer KB, Carromeu C, Griesi-Oliveira K, Muotri AR. Maintenance and differentiation of neural stem cells. Wiley Interdiscip Rev SystBiol Med.2011 Jan-Feb;3(1):107-14.
2.王畅,张艳军,冯英等.淫羊藿苷对短暂性前脑缺血模型大鼠海马神经再生的影响.中草药,2009,(5)：754-758
3.许亮.淫羊藿营对大鼠脑缺血再灌注后神经元的保护作用.临床神经病学杂志,2011,24(3)：198-201
4.柴丽娟,钟佩茹,周志焕.淫羊藿苷对体外神经干细胞增殖作用影响的研究.中国药理学通报,2010,26(5)：670-673
5.杨斌.淫羊覆苷药理研究概况[J].中国药房,2009,20(24)：1915-1917.
6. Sha D, Li L, Ye L, Liu R, Xu Y. Icariin inhibits neurotoxicity of beta-amyloid by upregulating cocaine-regulated and amphetamine-regulated transcripts. Neuroreport.2009 Nov 25;20 (17):1564-7.
7. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS. Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol.2007 Aug;34(8):792-5.
8.李梨.淫羊藿苷对缺血再灌致脑损伤保护作用的实验研究[D].重庆医科大学,2005.
9. Zeng KW, Fu H, Liu GX, Wang XM. Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-κB and JNK/p38 MAPK pathways[J]. Int Immunopharmacol,2010,10(6):668-678.
10.王晓云,王翀,黄嵘.淫羊藿苷对神经细胞缺血再灌注损害的保护作用及其机制研究[J].临床神经病学杂志,2012,25(5)：365-367.
11.魏海珍.齐墩果酸对损伤血管内皮细胞的保护作用及其机制探讨.南京医科大学学报：自然科学版,2012,32(11)：1505-1510
12.赵坚华,韩春姬.轮叶党参中的齐墩果酸对紫外线照射所诱发DNA损伤的保护作用.延边大学医学学报,2012,35(1)：22-24
13.汤华成,张东杰,赵蕾.功能性食品因子齐墩果酸研究进展.食品科技,2007,32(9)；16-18陈志辉,徐良梅,李建平.齐墩果酸研究进展.饲料博览,2010,(6)；7-9
14.张玉莲,刘爽.补肾中药有效成分对SAMP8小鼠海马APP及PS1基因表达的影响[J].天津中医药,2012,29(1)：59-61.
15.李春阳,李林,李宇航等.环烯醚萜苷对大鼠脑梗死后NF—KB与凋亡调节因子Bcl-2/Bax表达变化的影响[J].中国药理学通报,2006,22：19-22.
16.褚燕琦,李玮,李林等.山茱萸环烯醚萜苷对蛋白磷酸酶抑制剂冈田酸拟阿尔茨海默病细胞模型的作用[J].中国约理学通报,2006,22：960--963.
17.丁月霞,张丽,叶翠飞等.山茱萸环烯醚萜苷对穹隆海马伞切断大鼠海马区神经元存活和细胞凋亡调控因子的影响[J].首都医科大学学报,2011,32(1).
18.李小黎,王文,张丽等.山茱萸环烯醚帖苷对全脑缺血沙土鼠海马神经元凋亡相关因子的影响[J].吉林中医药,2010,30(9)
19. Kwon SH, Kim JA, Hong SI, Jung YH, Kim HC, Lee SY, Jang CG. Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK,p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem Int.2011 Mar;58(4):533-41.
20.王文,黄文婷,艾厚喜,李林,安易,刘茨.莫诺苷和马钱素对人神经母细胞瘤株SY5Y生长的影响[J].中国药理通讯,2007,24(2)：13-13.
21.张永强,程岗,章薇等.白藜芦醇对缺血再灌注小鼠神经干细胞增殖作用的研究[J].中华神经外科疾病研究杂志,2010,9(6)：484-487.
22.陈岩,李志伟,杨谦.丹参酮对大鼠脑缺血后神经干细胞增殖影响的研究[J].陕西医学杂志,2011,40(7)：774-775.
23.赵雪花.葛根素对大鼠脑缺血再灌注后Caspase-3和c-fos表达的影响[J].数理医药学杂志,2012,25(5)：511-512.
24.李志伟,穆英,郭荷娜等.葛根素对短暂性前脑缺血大鼠学习能力及神经干细胞增殖的影响[J].陕西医学杂志,2012,(11)：1454-1454.
25.杨谦,李志伟,穆英等.葛根素对去卵巢雌性大鼠脑内BDNF表达和神经干细胞增殖的影响[J].陕西医学杂志,2012,(7)：778-779.
26.张建平,司银楚.人参皂菅Rgl对成年大鼠脑缺血海马区神经干细胞的影响[J].第四军医大学学报,2008,29(24)：2225-2228.
27.崔荣太,蒲传强.人参皂甙Rgl对大鼠局灶性脑缺血后侧脑室下区神经干细胞增殖分化的影响[J].中华老年心脑血管病杂志,2007,9(10)：707-709.
28.崔荣太,蒲传强.人参皂甙Rgl对大鼠局灶性脑缺血脑组织神经干细胞增殖的影响[J].解放军医学杂志,2007,32(8)：842-845.
29.崔荣太,蒲传强.人参皂甙Rgl对体外培养大鼠神经干细胞的增殖作用[J].军医进修学院学报,2008,29(1)：22-22.
30.周志焕,王秀云,钟佩茹等.人参皂苷Rgl对体外培养胚胎神经干细胞增殖作用的影响[J].中国中医药信息杂志,2010,(2)：28-30.
31.庄朋伟,张艳军,庞坦.人参皂苷Rgl促进体外培养神经干细胞增殖的研究[J].中国中药杂j志,2009,(4)：443-446.
32.司银楚,李巾伟,张丽娟.三七总皂苷促进脑出血后侧脑室室管膜下神经干细胞的增殖和分化[J].中国组织工程研究与临床康复,2008,12(8)：1414-1417.
33.司银楚,成龙,洪庆涛等.三七总皂甙促进离体胎鼠皮层神经干细胞增殖、分化的实验研究[J].中国体视学与图像分析,2004,9(2)：78-83.
34.张建平,司银楚,朱培纯.三七总皂苷对体外培养的大鼠海马神经干细胞增殖分化的作用[J].解剖学报,2010,(3)：362-366.
35.王济潍,陈文,王玉良.EGb761对血管性痴呆大鼠海马齿状回神经干细胞增殖分化的影响[J].神经解剖学杂志,2012,28(6)：589-594.
36.李蕊,袁宝强,樊秋萍.银杏叶提取物对发育期戊四氮点燃癫痫大鼠学习记忆与海马神经干细胞增殖、分化的影响[J].实用儿科临床杂志,2011,26(23)：1821-1824.
37.张红梅,张琳,关涛.银杏叶提取物促进帕金森病模型小鼠窒管膜下区神经干细胞增殖作用的研究[J].世界中西医结合杂志,2008,3(9)：518-520.
38.张皓楠,王益民.银杏叶提取物对胎鼠皮质神经元细胞的影响[J].天津中医药大学学报,2012,31(4)：218-220.
39.李晓涛,路来金.银杏叶提取物对大鼠神经干细胞分化为神经元样细胞的影响[J].中国老年学杂志,2010,30(14)：2002-2003.
40.高诗豪,唐政恒,陈图南.蜕皮甾酮对大鼠脑组织自由基损伤的保护作用[J].第三军医大学学报,2012,34(23)：2357-2359.
41.陈月,李晓赫,陈福军等.β-蜕皮甾酮对匹罗卡品致痫小鼠海马神经元凋亡相关基因表达的影响[J].解剖科学进展,2012,18(1)：66-69
42.陈月,孟令慧,冯婉玉.β-蜕皮甾酮对APP/PS-1转基因小鼠学习记忆能力及海马Bel-2、 Bax蛋白表达的影响[J].解剖科学进展,2011,17(5)：440-444.
43.罗春霞,张映琦,迟路湘等.蜕皮甾酮对大鼠局灶性脑梗死的保护作用及机制初讨[J].西南国防医药,2009,19(2)：176-178.
44.储卫华,詹梦熊,朱刚等.EDS对新生SD大鼠海马神经干细胞增殖分化的作用[J].第三军医大学学报,2008,30(19)：1787-1790.