人参皂甙Rg1对海马神经前体细胞增殖能力的影响及其机制研究
摘要
中枢神经系统的大部分神经元处于终末分化状态，受损后无法再生。近年来，研究者在胚胎神经组织和成年脑内均找到了这样一群特殊的神经细胞，它们不但终生保有自我更新能力，而且还具备了多向分化的潜能，因而被称为“干细胞”或“前体细胞”。从理论上讲，这类细胞有可能能够替代那些由于疾病，外伤等原因而受到损害的神经元，因而有极大的应用前景。目前阶段，与此相关的研究主要集中在两个方面：1)从胚胎或成年脑组织中分离得到神经干细胞(NSCs)／神经前体细胞(NPCs)，在体外对其进行培养，扩增和某些基因操作，然后再将它们移植回受损的脑组织中；2)运用某些手段诱导体内的NSCs／NPCs发生增殖，分化，进而达到所谓“自我修复”的目的。十年来，以上两方面的研究工作吸引到了大批科学家的参与，并且都取得了一些突破性的进展。值得注意的是，这些工作大多以啮齿类动物为研究对象。一旦涉及到人类，神经干细胞的体外培养，移植等项工作便会遇到来源不足，不符合社会伦理道德观念等多方面的问题。因此，越来越多的研究者把目光转向了对体内干细胞进行诱导性操作这一方向。从药理学角度考虑，积极寻找能够影响NPCs增殖分化功能的化合物，无疑会为神经系统疾病的治疗打开一条全新的思路。
作为一种珍贵的滋补品，人参在中医中的应用已有了两千多年的历史。现代医学证明，人参具有促智，抗衰老等多种药理作用。人参皂甙Rgl是从人参中分离提取出的活性单体成分之一，它具备了人参促进学习记忆，延缓与衰老相关的功能低下等多项功效。本组以前的研究工作发现，Rgl能够通过促进脑内蛋白质合成，增加断乳小鼠脑皮层厚度和突触数目来提高啮齿类动物神经功能的可塑性。由于成年哺乳动物脑内NPCs的存在也被认为是一种神经可塑性的体现，可以设想，对脑内NPCs增殖分化状态产生影响很可能是Rgl发挥中枢药理作用的机制或途径之一。基于此，我们设计进行了本项实验，从体内外两个角度观察了Rgl对NPCs增殖，分化和存活等多项功能的影响。
Most neurons in CNS are terminally differentiated and are, thus, not replaced after neuronal cell death. However, self-renewing cells with multilineage potential, designated stem cells or progenitor cells, have been identified in both developing and adult brain in mammals. This finding raises the possibility that human neurons depleted by disease or injury could be replenished. At present, there are two active directions which have been studied in terms of using neural stem cells (NSCs) or neural progenitor cells (NPCs): 1) Isolate NSCs/NPCs from fetal or adult brain, expand, engineer them in vitro and then transplant them back to the injured brain. 2) Induce endogenous NSCs/NPCs to proliferate and differentiate in vivo to achieve self-repair. In the past decade, both subfields have attracted a large number of investigators and both have got promising results, especially in rodent. But when it comes to human being, the first group met with several difficulties ranging from ethical concerns to limited supply. So, it will be of great value to find out drugs that can affect the proliferation and /or differentiation ability of NPCs both in vitro and in vivo.
Ginseng has been used as a tonic in Chinese traditional medicine for over two thousand years. It has been proved to have various pharmacological actions on the CNS including nootropic and anti-aging effects. Ginsenoside Rg 1 is one of the most active ingredients in ginseng and shares many of its effects, such as facilitating learning, memory and alleviating age related decline of functions. In our previous studies, Rgl was found to accelerate protein biosynthesis, enhance the thickness of cortex and the density of synapses in rodent brain. As all above effects of Rgl had something to do with brain plasticity and the existence of NPCs in brain is also a new mechanism underlying functional plasticity of brain, it is possible that
作为一种珍贵的滋补品，人参在中医中的应用已有了两千多年的历史。现代医学证明，人参具有促智，抗衰老等多种药理作用。人参皂甙Rgl是从人参中分离提取出的活性单体成分之一，它具备了人参促进学习记忆，延缓与衰老相关的功能低下等多项功效。本组以前的研究工作发现，Rgl能够通过促进脑内蛋白质合成，增加断乳小鼠脑皮层厚度和突触数目来提高啮齿类动物神经功能的可塑性。由于成年哺乳动物脑内NPCs的存在也被认为是一种神经可塑性的体现，可以设想，对脑内NPCs增殖分化状态产生影响很可能是Rgl发挥中枢药理作用的机制或途径之一。基于此，我们设计进行了本项实验，从体内外两个角度观察了Rgl对NPCs增殖，分化和存活等多项功能的影响。
Most neurons in CNS are terminally differentiated and are, thus, not replaced after neuronal cell death. However, self-renewing cells with multilineage potential, designated stem cells or progenitor cells, have been identified in both developing and adult brain in mammals. This finding raises the possibility that human neurons depleted by disease or injury could be replenished. At present, there are two active directions which have been studied in terms of using neural stem cells (NSCs) or neural progenitor cells (NPCs): 1) Isolate NSCs/NPCs from fetal or adult brain, expand, engineer them in vitro and then transplant them back to the injured brain. 2) Induce endogenous NSCs/NPCs to proliferate and differentiate in vivo to achieve self-repair. In the past decade, both subfields have attracted a large number of investigators and both have got promising results, especially in rodent. But when it comes to human being, the first group met with several difficulties ranging from ethical concerns to limited supply. So, it will be of great value to find out drugs that can affect the proliferation and /or differentiation ability of NPCs both in vitro and in vivo.
Ginseng has been used as a tonic in Chinese traditional medicine for over two thousand years. It has been proved to have various pharmacological actions on the CNS including nootropic and anti-aging effects. Ginsenoside Rg 1 is one of the most active ingredients in ginseng and shares many of its effects, such as facilitating learning, memory and alleviating age related decline of functions. In our previous studies, Rgl was found to accelerate protein biosynthesis, enhance the thickness of cortex and the density of synapses in rodent brain. As all above effects of Rgl had something to do with brain plasticity and the existence of NPCs in brain is also a new mechanism underlying functional plasticity of brain, it is possible that
引文
1. Sah DW, Ray J, Gage FH, Bipotent progenitor cell lines from the human CNS. Nat Biotechnol, 1997, 15:574.
2. Chalmers-Redman RM, Priestley T, Kemp JA, et al, In vitro propagation and inducible differentiation of multipotential progenitor cells from human fetal brain. Neuroscience, 1997, 76:1121.
3. Pagano SF, Impagnatiello F, Girelli M, et al, Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem Cells, 2000, 18:295.
4. Roy NS, Wang S, Jiang L, et al, In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med, 2000, 6:271.
5. Caldwell MA, Svendsen CN. Heparin, but not other proteoglycans potentiates the mitogenic effects of FGF-2 on mesencephalic precursor cells. Experimental Neurology, 1998, 152: 1.
6. Vicario-Abejon C, Collin C, Tsoulfas P, et al, Hippocampal stem cells differentiate into excitatory and inhibitory neurons. Eur J Neurosci, 2000, 12:677.
7. Williams BP, Price J, Evidence for multiple precursor cell types in the embryonic rat cerebral cortex. Neuron, 1995, 14:1181.
8. Kilpatrick TJ, Bartlett PF, Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF. J Neurosci, 1995, 15:3653.9. Reynolds BA, Tetzlaff W, Weiss S, A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci, 1992, 12:4565.
10. Morshead CM, Reynolds BA, Craig CG, Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron, 1994, 13:1071.
11. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 1996, 16:2027.
12. Geuna S, Borrione P, Fornaro M et al, Adult stem cells and neurogenesis: historical roots and state of the art. Anat Rec (New Anat), 2001, 265:132.
13. Gage FH, Mammalian neural stem cells. Science, 2000, 287;1433.
14. Brewer GJ, Torricelli JR, Evege EK, Price PJ. Optimized survival of hippocampal neurons in B27-supplemented neurobasal, a new serum-free medium combination. J Neurosci Res, 1993,35:567-576.
15. Svendsen CN, Fawcett JW, Bentlage C, et al, Increased survival of rat EGF-generated CNS precursor cells using B27 supplemented medium. Exp Brain Res, 1995, 102:407.
16. Svendsen CN, Skepper J, Rosser AE, et al, Restricted growth potential of rat striatal precursors as compared to mouse. Dev Brain Res. 1997, 99: 253.
17. Ostenfeld T, Joly E, Tai YT, et al, Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res, 2002, 134: 43.
18. Lendahl U, Zimmerman LB, McKay RD, CNS stem cells express a new class of intermediate filament protein. Cell, 1990, 60: 585.
1. Kornak DR, Rakic O. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA, 1999, 96:5768.
2. Fuchs E, Gould E. In vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci, 2000, 12:2211.
3. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science, 264:1145.
4．申丽红，张均田。胎鼠神经干细胞培养方法的建立以及几种化合物对干细胞增殖能力的影响。药学学报(in press)。
5．张均田，刘云，屈志炜等，人参皂甙Rbl和Rgl对小鼠中枢神经递质受体和脑内蛋白质合成的影响。药学学报，1988，23：12。
6．杨迎，张均田，石成璋等，人参皂甙Rbl和Rgl促智作用机制的探讨。药学学报，1994，29：241。
7. Wang XY, Zhang JT. Effects of ginsenoside Rgl on synaptic plasticity of freely moving rats ans its mechanism of action. Acta Pharmacol Sin, 2001, 22: 657.
8. Altman J, Das GD, Autoradiographie and histological evidence of postnatal neurogenesis in rats. J Comp Neurol, 1965, 124, 319.
9. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med, 1998, 4: 1313.
10. Reynolds BA Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science, 1992, 255:1707.
11. Temple S. The development of neural stem cells. Nature, 2001, 414: 112.
12. Doetsch F, Caille I, Lira DA, Garcia-Verdugo JM, et al, Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 1999, 97: 703.
13. Barres BA. A new role for glia: generation of neurons! Cell, 1999.97: 667.
14. Malatesta P, Hartfuss E, Gotz M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development, 2000, 127: 5253.
15. Alvarez-Buylla A, Garcia-Verdugo JM, et al, A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci, 2001, 2: 287.
16. Gage FH. Mammalian neural stem cells. Science, 2000, 287: 1433.
17. Craig CG, Tropepe V, Morshead CM, et al, In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci, 1996, 16: 2649.18. Anderson MF, Aberg MA, Nilsson M, et al, Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res, 2002, 134: 115.
19. Walton MR, Dragunow I, Is CREB a key to neuronal survival? Trends Neurosci, 2000, 23: 48.
20. Nakagawa S, Kim JE, Lee R et al, Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein, J Neurosci, 2002, 22: 3673.
21. Liu M, Zhang JT. Effects of ginsenoside Rg1 on c-fos gene expression and cAMP levels in rat hippocampus, Acta Pharmacol Sin, 1996, 17:171.
22. Shors TJ, Miesegaes G, Beylin A, Neurogenesis in the adult is involved in the formation of trace memories. Nature, 2001, 410:372.
23. van Praag H, Schinder AF, Christie BR, Functional neurogenesis in the adult hippocampus. Nature,2002,415:1030.
24. Fallon J, Reid S, Kinyamu R, et al. In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA, 2000, 97:14686.
25. Haughey NJ, Liu D, Nath A, et al. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med, 2002, 1:125.
26. Armstrong RJ, Barker RA, Neurodegeneration: a failure of neuroregeneration? Lancet, 2000, 358:1174.
1. Cameron HA, Hazel TG, McKay RD. Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol, 1998, 36: 287.
2. Kuhn HG, Winkler J, Kempermann G, Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci, 1997, 17: 5820.
3. Gould E, Cameron HA, McEwen BS. Blockade of NMDA receptors increase cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340:551.
4. Kempermann G, Kuhn HG, Gage FH, More hippocampal neurons in adult mice living in an enriched environment. Nature, 1997, 386: 493.
5. van Praag H, Christie BR, Sejnowski TJ, Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A, 1999, 96: 13427.
6. Gould E, Beylin A, Tanapat P, Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 1999, 2: 260.
7. Cameron HA, Tanapat P, Gould E. Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience, 1998, 82: 349.
8. Madeira MD, Cadete-Leite A, Andrade JP, Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol, 1991, 314: 171.
9. Kempermann G, Kuhn HG, Gage FH, Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci, 1998, 18: 3206.
10. Liu J, Solway K, Messing RO, Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci, 1998, 18: 7768.
11. Zhang RL, Zhang ZG, Zhang L, et al, Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience, 2001, 105: 33.
12. Dash PK, Mach SA, Moore AN, Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res, 2001, 63: 313.
13. Parent JM, Valentin VV, Lowenstein DH, Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactorybulb pathway. J Neurosci,2002, 22: 3174.
14. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 1984, 11: 47.
15. Wiard RP, Dickerson MC, Beek O, et al. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke, 1995, 26, 466.
16. Feng YP, Yan CH. Animal models of cerebral ischemia. Zhang JT, Modern Experimental Methods in Pharmacology. Peking: Peking medical University、Peking Union Medical University Press, 1998. 1244.
17. Gill R, Woodruff GN. The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia, Eur J Pharmacol, 1990, 176: 143.
18. Bernabeu R, Sharp FR. NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab, 2000, 20:1669.
19. Morshead CM, van der Kooy D, Postmitotic death is the fate of constitutively proliferating cells in the subependymal layer of the adult mouse brain. J Neurosci, 1992, 12: 249.
20. Biebl M, Cooper CM, Winkler J, et al, Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett, 2000, 291: 17.
21. Shetty AK, Turner DA. In vitro survival and differentiation of neurons derived from epidermal growth factor-responsive postnatal hippocampal stem cells: inducing effects of brain-derived neurotrophic factor. J Neurobiol, 1998, 35: 395.
22. Benoit BO, Savarese T, Joly M, Neurotrophin channeling of neural progenitor cell differentiation. J Neurobiol, 2001, 46: 265.
23. Seaberg RM, van der Kooy D., Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci, 2002, 22: 1784
24. Kee NJ, Preston E, Wojtowicz J.M, Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Exp Brain Res, 2001, 136: 313
25. Takagi Y, Nozaki K, Takahashi J, Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res, 1999, 831: 283.
26. Hastings NB, Gould E, Adult-generated granule cells rapidly extend axonsinto the CA3 region: a combined BrdU-labeling and retrograde tracer study, J Comp Neurol, 1999, 413: 146.
27. Squire LR, Zola SM, Ischemic brain damage and memory impairment: a commentary. Hippocampus, 1996, 6: 546.
28. Cameron HA, Woolley CS, McEwen BS, et al, Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience, 1993, 56: 337.
29. Zhang R, Zhang L, Zhang Z, et al, A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol, 2001, 50: 602.
30. Zhu DY, Liu SH, Sun HS, et al, Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus, J Neurosci, 2003, 23: 223.
31. Gould E, Cameron HA, McEwen BS, Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340: 551.
32. Nacher J, Rosell DR, Alonso-Llosa G, et al, NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci, 2001, 13: 512.
33. Nacher J, Alonso-Llosa G, Rosell DR, et al, NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging, 2003, 24: 273.
34. Arvidsson A, Kokaia Z, Lindvall O, N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci, 2001, 14: 10.
35. Mori K, Togashi H, Ueno KI, et al, Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia. Behav Brain Res, 200, 120: 159.
36. Papa M, Pellicano MP, Sadile AG, Nitric oxide and long-term habituation to novelty in the rat, Ann N Y Acad Sci, 1994, 738: 316.
37. Mani S, Shen Y, Schaefer J, et al, Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons, Mol Cell.Neurosci, 2001, 17, 1754.
38. Wang XY Zhang JT, Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action,Acta. Pharmacol. Sin, 2001, 22: 1099.
39. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation, J Neurosci, 1996, 16: 2027.
40. Shors TJ, Miesegaes G, Beylin A, et al, Neurogenesis in the adult is involved in the formation of trace memories, Nature, 2001, 410: 372.
41. Haughey NJ, Liu D, Nath A, et al, Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease, Neuromolecular Med, 202, 1: 125.
1. Fuchs E, Segre JA, Stem cells: a new lease on life, Cell, 2000, 100: 143.
2. Altman J, Das GD, Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol, 1965, 124: 319.
3. Reynolds BA, Tetzlaff W, Weiss S, A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci, 1992, 12: 4565.
4. Richards LJ, Kilpatrick TJ, Bartlett PF, De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A, 1992, 89: 8591.
5. Temple S, CNS development: The obscure origins of adult stem cells. Curr Biol, 1999, 9: R397.
6. Johe KK, Hazel TG, Muller T, et al, Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev, 1996, 10: 3129.
7. Weiss S, Dunne C, Hewson J, Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16: 7599.
8. Palmer TD, Ray J, Gage FH, FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci, 1995, 6: 474.
9. del Rio JA, Soriano E, Immunocytochemical detection of 5'- bromodeoxyuridine incorporation in the central nervous system of the mouse. Brain Res Dev Brain Res, 1989, 49: 311.
10. Cooper-Kuhn CM, Kuhn HG, Is it all DNA repair? Methodological considerations for detecting neurogenesis in the adult brain. Brain Res Dev Brain Res, 2002, 134: 13.
11. Brooks PJ, Marietta C, Goldman D, DNA mismatch repair and DNA methylation in adult brain neurons. J Neurosci, 1996, 16: 939.
12. Takahashi T, Nowakowski RS, Caviness VS Jr, BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone. J Neurocytol, 1992, 21: 185.
13. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 1996, 16: 2027.
14. Gould E, The effects of adrenal steroids and excitatory input on neuronalbirth and survival. Ann N Y Acad Sci, 1994, 743: 73.
15. Nilsson M, Perfilieva E, Johansson U, Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol, 1999, 39: 569.
16. van Praag H, Christie BR, Sejnowski TJ, Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A, 1999, 96: 13427.
17. Sharp FR, Liu J, Bernabeu R, Neurogenesis following brain ischemia. Brain Res Dev Brain Res, 2002, 134: 23.
18. Parent JM, The role of seizure-induced neurogenesis in epileptogenesis and brain repair, Epilepsy Res, 2002, 50: 179.
19. Gould E, Tanapat P, Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience, 1997,80:427.
20. Magavi SS, Macklis JD, Induction of neuronal type-specific neurogenesis in the cerebral cortex of adult mice: manipulation of neural precursors in situ. Brain Res Dev Brain Res, 2002, 134: 57.
21. Nakatomi H, Kuriu T, Okabe S, Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell, 2002, 110: 429.
22. Kruger GM, Morrison SJ, Brain repair by endogenous progenitors. Cell, 2002, 110: 399.
23. Gould E, Cameron HA, McEwen BS, Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340: 551.
24. Nacher J, Rosell DR, Alonso-Llosa G, et al, NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci, 2001, 13: 512.
25. Nacher J, Alonso-Llosa G, Rosell DR, et al, NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging, 2003, 24: 273.
26. Arvidsson A, Kokaia Z, Lindvall O, N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci, 2001, 14: 10.
27. Bernabeu R, Sharp FR, NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab 2000, 20: 1669.
28. Zigova T, Pencea V, Wiegand SJ, et al, Intraventricular administration of BDNF increases the number of newly generated neurons in the adultolfactory bulb. Mol Cell Neurosci, 1998, 11: 234.
29. Uchida N, Kiuchi Y, Miyamoto K, Glutamate-stimulated proliferation of rat retinal pigment epithelial cells. Eur J Pharmacol, 1998, 343: 265.
30. Zhang R, Zhang L, Zhang Z, et al, A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol, 2001, 50: 602.
31. Zhu DY, Liu SH, Sun HS, et al, Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyms. J Neurosci, 2003, 23: 223.
32. Mani S, Shen Y, Schaefer J, et al, Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons. Mol Cell.Neurosci, 2001, 17, 1754.
33. Wang XY Zhang JT, Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta. Pharmacol. Sin, 2001, 22: 1099.
34. Walton MR, Dragunow I, Is CREB a key to neuronal survival? Trends Neurosci, 2000, 23: 48.
35. Nakagawa S, Kim JE, Lee R et al, Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci, 2002, 22: 3673.
36. Liu M, Zhang JT. Effects of ginsenoside Rg1 on c-fos gene expression and cAMP levels in rat hippocampus. Acta Pharmacol Sin, 1996, 17:171
37. Mabuchi T, Kitagawa K, Kuwabara K, Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J Neurosci, 2001, 21: 9204.
38. Gould E, Beylin A, Tanapat P, Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 1999, 2: 260.
39. Shors TJ, Miesegaes G, Beylin A, Neurogenesis in the adult is involved in the formation of trace memories. Nature, 2001,410: 372.
40. Haughey NJ, Nath A, Chan SL, Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem, 2002, 83: 1509.
41. Hodges H, Veizovic T, Bray N, Conditionally immortal neuroepithelial stem cell grafts reverse age-associated memory impairments in rats. Neuroscience, 2000,101: 945.
1. Kennedy M, Firpo M, Chol K, et al, A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature, 1997, 386: 488.
2. Burt RK. Clinical utility in maximizing CD34~+ cell count in stem cell grafts. Stem cells, 1999, 17:373.
3. Wagner JE, Kernan NA, Steinbuch M, et al, Allogeneic sibling umbilical-cord-blood transplantation in chidren with malignant and non-malignant disease. The Lancet, 1995, 346: 214.
4. Pittenger MF, Mackay AM, Beck SC, Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284: 143.
5. Ferrari G, Angelis GC, Colletta M, et al, Muscle regeneration by bone marrow-derived myogenic progenitors. Science, 1998, 279: 1528.
6. Krause DS, Theise ND, Collector MI, et al, Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 2001, 105: 369.
7. Jones PH, Harper S, Watt FM. Stem cell pattering and fate in human epidermis. Cell, 1995, 80: 83.
8. Taylor G, Lehrer MS, Jensen PJ, et al, Involvement of follicullar stem cells in forming not only the follicle but also the epidermis. Cell, 2000, 120: 451.
9. Pellegrini G, Traverso CE, Franzi AT, et al, Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. The Lancet, 1997, 349, 990.
10. Schwab IR, Reyes M, Isseroff RR, Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea, 2000, 19: 421.
11. Gage FH, Mammalian neural stem cells, Science, 2000, 287, 1433.
12. Renfranz PJ, Cunningham MG, Ronald DG Mckay, Region - specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell, 1991, 66: 731.
13. Bartlett PF, Reid HH, Bailey KA, et al, Immortalization of mouse neural precursor cells by the c-myc oncogene. Proc Natl Acad Sci USA, 1988, 85: 3255.
14. Sah DW, Ray J, Gage FH, Biopotent progenitor cell lines from the human CNS. Nat Biotechnol, 1997,15: 574.
15. Chalmers-Redman RM, Priestley T, In vitro propagation and inducible differentiation of multipotential progenitor cells from human fetal brain.Neuroscience, 1997, 76: 1121.
16. Paganoa SF, Impagnatiellob F, Girellia M, et al, Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem cells, 2000, 18: 295.
17. Roy NS, Wang S, Jiang L, In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med, 2000, 6: 271.
18. Brannen CL, Sugaya K, In vitro differentiation of multipotent human neural progenitors in serum-free medium. Neuroreport 2000, 11:1123.
19. Gottlieb DI, Huettner JE, An in vitro pathway from embryonic stem cells to neurons and glia. Cells Tissues Organs, 1999, 165:165.
20. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Embryonic stem cell lines derived from human blastocysts. Science, 1998, 282:1145.
21. Shamblott MJ, Axelman J, Wang S, Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A, 1998, 95:13726.
22. Laywell ED, Kukekov VG, Steindler DA, Multipotent neurospheres can be derived from forebrain subependymal zone and spinal cord of adult mice after protracted postmortem intervals. Exp Neurol, 1999, 156:430.
23. Palmer TD, Schwartz PH, Taupin P, et al, Cell culture. Progenitor cells from human brain after death. Nature, 2001, 411:42.
24. Sohonen JO, Peterson DA, Ray J, et al, Differentiation of adult hippocampus - derived progenitors into olfactory neurons in vivo. Nature, 1996, 383: 624.
25. Martinez-Serrano A, Lundberg CHP, Fischer W, et al, CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: complete rescue of axotomized cholinergic neurons after transplantation into the septum. J Neurosci, 1995, 15: 5668.
26. Lindvall O, Brundin P, Widner H, et al, Grafts of fetal Dopamine Neurons survive and improve motor function in Parkinson's Disease. Science, 1990, 247: 574.
27. Freeman TB, Cicchetti F, Hauser RA, et al, Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc Natl Acad Sci U S A, 2000, 97:13877.
28. Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature, 2000, 405: 951.
29. Kempermann G, Kuhn HG, Gage FH, More hippocampal neurons in adultmice living in an enriched environment. Nature, 386; 493.
30. Tanapat P, Galea Liisa AM, Gould E, et al, Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci, 1998,16: 235.
31. Craig CG, Tropepe V, Morshead CM, In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci, 1996, 16: 2649.
32. Aberg MA, Aberg ND, Hedbacker H, et al, Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci, 2000, 20:2896.
33. Haydar TF, Wang F, Schwartz ML, et al, Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci, 2000, 20:5764.
34. Bjornson CR, Rietze RL, Reynolds BA, et al, Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science, 1999, 283:534.
35. Woodbury D, Schwarz EM, Prockop DJ, et al, Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res, 2000, 61: 364.
36. Kondo T, Raff M, Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science, 2000, 289:1754.
[1] Chang SY et al. (1988) Memory facilitation induced by gynostemma, pentaphyllum and gypensode III (ginsenoside b1) in mice.Chin pharmacol Bull, 4, 358-61.
[2] Zhang JT et al. (1990) Preliminary study on antiamnestic mechanism of ginsenoside Rg1 and Rb1. Chin Med J 130, 932-8.
[3] Qiu Y et al. (1995) Protective effects of ginsenoside on the learning and memory impairment induced by transient cerebral ischemia-reperfusion in mice. Chin Pharmacol Bull 11, 299-302.
[4] Zhang DS and Zhang JT. (2000) Effects of total ginsenoside on learning and memory impairment induced by beta-amyloid peptide(25-35). Chin Pharmacol Bull 16, 422-5.
[5] Wang XY and Zhang JT. (2001) Effects of ginenoside Rg1 on learning and memory impairment induced by. Ada Pharmaceu Sin 36, 1-4.
[6] Gong YS and Zhang JT. (1999) Effect of 17 - estradiol and ginsenoside Rg1 on reactive microglia induced by. J Asian Nat Prod Res 17, 153-61.
[7] Chen J et al. Effects of 17 estradiol and total ginsenoside on the spatial learning and memory impairment of ovariectomy rats. Chin Med J 36, 522-6.
[8] Zhang DS and Zhang JT. (2000) Effect of total ginsenoside on synaptic transmission in dentate gyrus in rats. Acta Pharmaceu Sin 35, 185-8.
[9] Wang XY and Zhang JT. (2001) NO mediates ginsenoside Rg1-induced long-term potentiation in anesthetized rats. Acta Pharmacol Sin 22, 657-62.
[10] Wang XY and Zhang JT. (2001) Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta Pharmacol Sin 22, 1099-102.
[11] Zhang JT et al. (1988) Influence of ginsenoside Rb1 and Rg1 on some central neurotransmitter receptors and protein biosynthesis in mouse brain. Acta Pharmaceu Sin 23, 12-6.
[12] Liu M and Zhang JT. (1996) Influence of ginsenoside Rb1 and Rg1 on some central neurotransmitter receptors and protein biosynthesis in mouse brain. Acta Pharmacol Sin 17, 171-4.
[13] Yang Y et al. (1994) Study on the nootropic mechanism of ginsenoside Rb1 and Rg1---influence on mouse brain development. Acta Pharmaceu Sin 29, 241-5.
[14] Lian XY and Zhang JT. (1998) Effect of ginsenoside Rb1 on repeated stress-induced sexual deficiencies in male mice. Acta Pharmaceu Sin 33, 184-7.
[15] Wang XY and Zhang JT. (2002) Effect of ginsenoside Rb1 on mouse sexual function and its mechanism. Acta Pharmaceu Sin 35, 492-5.
[16] Lian XY and Zhang JT. (2001) Chronic stress and gonadectomy decrease the levels of neurotrophin-3 and brain-derived neurotrophic factor in adult mouse brain. Chin J Pharmacol Toxicol 15, 245-50.
[17] Li JQ et al. (1997) Inhibition of apoptosis by ginsenoside Rg1 in cultured cortical neurons. Chin Med J 32, 406-10.
[18] Li JQ et al. (1997) Effect of age and ginsenoside Rg1 on nitric oxide content and nitric oxide synthase activity of cerebral cortex on rats. Acta Pharmaceu Sin 32, 251-4.
[19] Liu M and Zhang JT. (2002) The immunoregulatory effects of ginsenoside Rg1 in aged rats. Acta Pharmaceu Sin 30, 818-23.
[20] Liu M and Zhang JT. (1996) Studies on the mechanisms of immunoregulatory effects of ginsenoside Rg1 in aged rats. Acta Pharmaceu Sin 31, 95-100.
[21] Gage FH. (2000) Mammalian neural stem cells. Cell 60, 585-95.
[22] Kuhn HG et al. (1996) Neurogenesis in thedentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16, 2027-33.
[23] Shors TJ et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372-6.
[24] Haughey NJ et al. (2002) Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med 1, 125-35.
[25] Shen LH and Zhang JT. (2002) Effects of ginsenoside Rg1 on neural progenitors' proliferation ability. 8~(th) Inter Symposium Ginseng, 2002, Seoul, Korean, 522.
[26] Shen LH, Zhang JT. (2003) Ginsenoside Rg1 increases ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils. Neurosci Lett, 344:1-4.
[27] Teng CM et al. (1989) Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng. Biochim Biophys Acta 990, 315-20.
[28] Kimura Y et al. (1988) Effects of various ginseng saponins on 5-hydroxytryptamine release and aggregation in human platelets. J Pharm Pharmacol 40, 838-43.
[29] Wu W et al. (1995) Effects of Panax notoginseng saponin Rg1 on cardiac electrophysiological properties and ventricular fibrillation threshold in dogs. Chin Pharmaceu Bull 16, 459-63.
[30] Zhang RB et al. (1982) Cardiac arrhythmia induced by hypothalamic stimulation in cardiac ischemic rabbits and the antiarrhythmic action of Panax ginseng. Chin Pharmaceu Bull 3, 226-30.
[31] Ikehara M et al. (1978) Effect of ginseng saponins on cholesterol metabolism. III. Effect of ginsenoside-Rb on cholesterol synthesis in rats fed on high-fat diet. Chem Pharm Bull 26, 2844-54.
[32] Kang SY et al. (1995) Dietary ginsenosides improve endothelium-dependent relaxation in the thoracic aorta of hypercholesterolemic rabbit. Gen Pharmacol 26, 483-7.
[33] Park KH et al. (2002) Possible role of ginsenoside Rb1 on regulation of rat liver triglycerides. Biol Pharm Bull 25, 457-60.
[34] Attele AS et al. (2002) Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 51, 1851-8.
[35] Kang KS et al. (2000) Preventive effect of epicatechin and ginsenoside Rb(2) on the inhibition of gap junctional intercellular communication by TPA and H(2)O(2). Cancer Lett 152, 97-106.
[36] Ota T et al. (1997) G1 phase-specific suppression of the Cdk2 activity by ginsenoside Rh2 in cultured murine cells. Life Sci 60, PL39-44.
[37] Han R. (2002) Highlight on the studies of anticancer drugs derived from plants in China. Stem cells 12, 53-63.
[38] Zhang JT. (1995) The retrospection and prospect of ginseng research. Acta Pharmaceu Sin 30, 321-5.
[39] Dou DQ et al. (1999) Advances and prospects of the study on chmical constituents and pharmacological activities of Panax ginseng. J Shenyang Pharmaceu University 16, 321-5.
[40] Huang YS et al. (1989) Effect of ginsenoside Rb1 and Rg1 on lipid peroxidation of rat in vitro. Acta Academiae Medicinae Sinicae 11, 460-2.
[41] Deng HL and Zhang JT. (1991) Anti-lipid peroxydative effect of ginsenoside Rb1 and Rg1. Chin Med J 11, 395-8.
[42] Liu M and Zhang JT. Effects of ginsenoside Rb1 and Rg1 on synaptosomal free calcium level, ATPase and calmudulin in rat hippocampus. Chin Med J 108, 544-7.
[43] Jiang XY et al. (1996) Mechanism of action of ginsenoside Rb1 in decreasing intracellular Ca~(2+). Acta Pharmaceu Sin 31, 321-6.
[44] Liu M and Zhang JT. (1995) Protective effects of ginsenoside Rb1 and Rg1 in cultured hippocampal neurons. Acta Pharmaceu Sin 30, 674-8.
[45] Wang JH et al. (2001) Triterpenoid saponins from leaves and stems of Panax quinquefolium L. J Asian Nat Prod Res 3, 293-7.
[46] Yang XW et al. (2000) Ginsenoside-Rg6, a novel triterpenoid saponin from the stem-leaves of Panax ginseng C.A.Mey. Chin Chem Lett 11, 909-12.
[47] Le Tran Ouan et al. (2001) Triterpene saponins from Vietnamese Ginseng (Panax vietnamensis) and their hepatocytoprotective activities. J Nat Prod 64, 456-61.
[48] Dou DQ et al. (2001) Six new dammarane-type triterpene saponins from the leaves of Panax ginseng. Chem Pharm Bull 49, 442-6.
2. Chalmers-Redman RM, Priestley T, Kemp JA, et al, In vitro propagation and inducible differentiation of multipotential progenitor cells from human fetal brain. Neuroscience, 1997, 76:1121.
3. Pagano SF, Impagnatiello F, Girelli M, et al, Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem Cells, 2000, 18:295.
4. Roy NS, Wang S, Jiang L, et al, In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med, 2000, 6:271.
5. Caldwell MA, Svendsen CN. Heparin, but not other proteoglycans potentiates the mitogenic effects of FGF-2 on mesencephalic precursor cells. Experimental Neurology, 1998, 152: 1.
6. Vicario-Abejon C, Collin C, Tsoulfas P, et al, Hippocampal stem cells differentiate into excitatory and inhibitory neurons. Eur J Neurosci, 2000, 12:677.
7. Williams BP, Price J, Evidence for multiple precursor cell types in the embryonic rat cerebral cortex. Neuron, 1995, 14:1181.
8. Kilpatrick TJ, Bartlett PF, Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF. J Neurosci, 1995, 15:3653.9. Reynolds BA, Tetzlaff W, Weiss S, A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci, 1992, 12:4565.
10. Morshead CM, Reynolds BA, Craig CG, Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron, 1994, 13:1071.
11. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 1996, 16:2027.
12. Geuna S, Borrione P, Fornaro M et al, Adult stem cells and neurogenesis: historical roots and state of the art. Anat Rec (New Anat), 2001, 265:132.
13. Gage FH, Mammalian neural stem cells. Science, 2000, 287;1433.
14. Brewer GJ, Torricelli JR, Evege EK, Price PJ. Optimized survival of hippocampal neurons in B27-supplemented neurobasal, a new serum-free medium combination. J Neurosci Res, 1993,35:567-576.
15. Svendsen CN, Fawcett JW, Bentlage C, et al, Increased survival of rat EGF-generated CNS precursor cells using B27 supplemented medium. Exp Brain Res, 1995, 102:407.
16. Svendsen CN, Skepper J, Rosser AE, et al, Restricted growth potential of rat striatal precursors as compared to mouse. Dev Brain Res. 1997, 99: 253.
17. Ostenfeld T, Joly E, Tai YT, et al, Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res, 2002, 134: 43.
18. Lendahl U, Zimmerman LB, McKay RD, CNS stem cells express a new class of intermediate filament protein. Cell, 1990, 60: 585.
1. Kornak DR, Rakic O. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA, 1999, 96:5768.
2. Fuchs E, Gould E. In vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci, 2000, 12:2211.
3. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science, 264:1145.
4．申丽红，张均田。胎鼠神经干细胞培养方法的建立以及几种化合物对干细胞增殖能力的影响。药学学报(in press)。
5．张均田，刘云，屈志炜等，人参皂甙Rbl和Rgl对小鼠中枢神经递质受体和脑内蛋白质合成的影响。药学学报，1988，23：12。
6．杨迎，张均田，石成璋等，人参皂甙Rbl和Rgl促智作用机制的探讨。药学学报，1994，29：241。
7. Wang XY, Zhang JT. Effects of ginsenoside Rgl on synaptic plasticity of freely moving rats ans its mechanism of action. Acta Pharmacol Sin, 2001, 22: 657.
8. Altman J, Das GD, Autoradiographie and histological evidence of postnatal neurogenesis in rats. J Comp Neurol, 1965, 124, 319.
9. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med, 1998, 4: 1313.
10. Reynolds BA Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science, 1992, 255:1707.
11. Temple S. The development of neural stem cells. Nature, 2001, 414: 112.
12. Doetsch F, Caille I, Lira DA, Garcia-Verdugo JM, et al, Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 1999, 97: 703.
13. Barres BA. A new role for glia: generation of neurons! Cell, 1999.97: 667.
14. Malatesta P, Hartfuss E, Gotz M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development, 2000, 127: 5253.
15. Alvarez-Buylla A, Garcia-Verdugo JM, et al, A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci, 2001, 2: 287.
16. Gage FH. Mammalian neural stem cells. Science, 2000, 287: 1433.
17. Craig CG, Tropepe V, Morshead CM, et al, In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci, 1996, 16: 2649.18. Anderson MF, Aberg MA, Nilsson M, et al, Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res, 2002, 134: 115.
19. Walton MR, Dragunow I, Is CREB a key to neuronal survival? Trends Neurosci, 2000, 23: 48.
20. Nakagawa S, Kim JE, Lee R et al, Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein, J Neurosci, 2002, 22: 3673.
21. Liu M, Zhang JT. Effects of ginsenoside Rg1 on c-fos gene expression and cAMP levels in rat hippocampus, Acta Pharmacol Sin, 1996, 17:171.
22. Shors TJ, Miesegaes G, Beylin A, Neurogenesis in the adult is involved in the formation of trace memories. Nature, 2001, 410:372.
23. van Praag H, Schinder AF, Christie BR, Functional neurogenesis in the adult hippocampus. Nature,2002,415:1030.
24. Fallon J, Reid S, Kinyamu R, et al. In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA, 2000, 97:14686.
25. Haughey NJ, Liu D, Nath A, et al. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med, 2002, 1:125.
26. Armstrong RJ, Barker RA, Neurodegeneration: a failure of neuroregeneration? Lancet, 2000, 358:1174.
1. Cameron HA, Hazel TG, McKay RD. Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol, 1998, 36: 287.
2. Kuhn HG, Winkler J, Kempermann G, Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci, 1997, 17: 5820.
3. Gould E, Cameron HA, McEwen BS. Blockade of NMDA receptors increase cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340:551.
4. Kempermann G, Kuhn HG, Gage FH, More hippocampal neurons in adult mice living in an enriched environment. Nature, 1997, 386: 493.
5. van Praag H, Christie BR, Sejnowski TJ, Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A, 1999, 96: 13427.
6. Gould E, Beylin A, Tanapat P, Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 1999, 2: 260.
7. Cameron HA, Tanapat P, Gould E. Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience, 1998, 82: 349.
8. Madeira MD, Cadete-Leite A, Andrade JP, Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol, 1991, 314: 171.
9. Kempermann G, Kuhn HG, Gage FH, Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci, 1998, 18: 3206.
10. Liu J, Solway K, Messing RO, Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci, 1998, 18: 7768.
11. Zhang RL, Zhang ZG, Zhang L, et al, Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience, 2001, 105: 33.
12. Dash PK, Mach SA, Moore AN, Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res, 2001, 63: 313.
13. Parent JM, Valentin VV, Lowenstein DH, Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactorybulb pathway. J Neurosci,2002, 22: 3174.
14. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 1984, 11: 47.
15. Wiard RP, Dickerson MC, Beek O, et al. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke, 1995, 26, 466.
16. Feng YP, Yan CH. Animal models of cerebral ischemia. Zhang JT, Modern Experimental Methods in Pharmacology. Peking: Peking medical University、Peking Union Medical University Press, 1998. 1244.
17. Gill R, Woodruff GN. The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia, Eur J Pharmacol, 1990, 176: 143.
18. Bernabeu R, Sharp FR. NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab, 2000, 20:1669.
19. Morshead CM, van der Kooy D, Postmitotic death is the fate of constitutively proliferating cells in the subependymal layer of the adult mouse brain. J Neurosci, 1992, 12: 249.
20. Biebl M, Cooper CM, Winkler J, et al, Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett, 2000, 291: 17.
21. Shetty AK, Turner DA. In vitro survival and differentiation of neurons derived from epidermal growth factor-responsive postnatal hippocampal stem cells: inducing effects of brain-derived neurotrophic factor. J Neurobiol, 1998, 35: 395.
22. Benoit BO, Savarese T, Joly M, Neurotrophin channeling of neural progenitor cell differentiation. J Neurobiol, 2001, 46: 265.
23. Seaberg RM, van der Kooy D., Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci, 2002, 22: 1784
24. Kee NJ, Preston E, Wojtowicz J.M, Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Exp Brain Res, 2001, 136: 313
25. Takagi Y, Nozaki K, Takahashi J, Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res, 1999, 831: 283.
26. Hastings NB, Gould E, Adult-generated granule cells rapidly extend axonsinto the CA3 region: a combined BrdU-labeling and retrograde tracer study, J Comp Neurol, 1999, 413: 146.
27. Squire LR, Zola SM, Ischemic brain damage and memory impairment: a commentary. Hippocampus, 1996, 6: 546.
28. Cameron HA, Woolley CS, McEwen BS, et al, Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience, 1993, 56: 337.
29. Zhang R, Zhang L, Zhang Z, et al, A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol, 2001, 50: 602.
30. Zhu DY, Liu SH, Sun HS, et al, Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus, J Neurosci, 2003, 23: 223.
31. Gould E, Cameron HA, McEwen BS, Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340: 551.
32. Nacher J, Rosell DR, Alonso-Llosa G, et al, NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci, 2001, 13: 512.
33. Nacher J, Alonso-Llosa G, Rosell DR, et al, NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging, 2003, 24: 273.
34. Arvidsson A, Kokaia Z, Lindvall O, N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci, 2001, 14: 10.
35. Mori K, Togashi H, Ueno KI, et al, Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia. Behav Brain Res, 200, 120: 159.
36. Papa M, Pellicano MP, Sadile AG, Nitric oxide and long-term habituation to novelty in the rat, Ann N Y Acad Sci, 1994, 738: 316.
37. Mani S, Shen Y, Schaefer J, et al, Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons, Mol Cell.Neurosci, 2001, 17, 1754.
38. Wang XY Zhang JT, Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action,Acta. Pharmacol. Sin, 2001, 22: 1099.
39. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation, J Neurosci, 1996, 16: 2027.
40. Shors TJ, Miesegaes G, Beylin A, et al, Neurogenesis in the adult is involved in the formation of trace memories, Nature, 2001, 410: 372.
41. Haughey NJ, Liu D, Nath A, et al, Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease, Neuromolecular Med, 202, 1: 125.
1. Fuchs E, Segre JA, Stem cells: a new lease on life, Cell, 2000, 100: 143.
2. Altman J, Das GD, Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol, 1965, 124: 319.
3. Reynolds BA, Tetzlaff W, Weiss S, A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci, 1992, 12: 4565.
4. Richards LJ, Kilpatrick TJ, Bartlett PF, De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A, 1992, 89: 8591.
5. Temple S, CNS development: The obscure origins of adult stem cells. Curr Biol, 1999, 9: R397.
6. Johe KK, Hazel TG, Muller T, et al, Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev, 1996, 10: 3129.
7. Weiss S, Dunne C, Hewson J, Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16: 7599.
8. Palmer TD, Ray J, Gage FH, FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci, 1995, 6: 474.
9. del Rio JA, Soriano E, Immunocytochemical detection of 5'- bromodeoxyuridine incorporation in the central nervous system of the mouse. Brain Res Dev Brain Res, 1989, 49: 311.
10. Cooper-Kuhn CM, Kuhn HG, Is it all DNA repair? Methodological considerations for detecting neurogenesis in the adult brain. Brain Res Dev Brain Res, 2002, 134: 13.
11. Brooks PJ, Marietta C, Goldman D, DNA mismatch repair and DNA methylation in adult brain neurons. J Neurosci, 1996, 16: 939.
12. Takahashi T, Nowakowski RS, Caviness VS Jr, BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone. J Neurocytol, 1992, 21: 185.
13. Kuhn HG, Dickinson-Anson H, Gage FH, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 1996, 16: 2027.
14. Gould E, The effects of adrenal steroids and excitatory input on neuronalbirth and survival. Ann N Y Acad Sci, 1994, 743: 73.
15. Nilsson M, Perfilieva E, Johansson U, Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol, 1999, 39: 569.
16. van Praag H, Christie BR, Sejnowski TJ, Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A, 1999, 96: 13427.
17. Sharp FR, Liu J, Bernabeu R, Neurogenesis following brain ischemia. Brain Res Dev Brain Res, 2002, 134: 23.
18. Parent JM, The role of seizure-induced neurogenesis in epileptogenesis and brain repair, Epilepsy Res, 2002, 50: 179.
19. Gould E, Tanapat P, Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience, 1997,80:427.
20. Magavi SS, Macklis JD, Induction of neuronal type-specific neurogenesis in the cerebral cortex of adult mice: manipulation of neural precursors in situ. Brain Res Dev Brain Res, 2002, 134: 57.
21. Nakatomi H, Kuriu T, Okabe S, Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell, 2002, 110: 429.
22. Kruger GM, Morrison SJ, Brain repair by endogenous progenitors. Cell, 2002, 110: 399.
23. Gould E, Cameron HA, McEwen BS, Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus. J Comp Neurol, 1994, 340: 551.
24. Nacher J, Rosell DR, Alonso-Llosa G, et al, NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci, 2001, 13: 512.
25. Nacher J, Alonso-Llosa G, Rosell DR, et al, NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging, 2003, 24: 273.
26. Arvidsson A, Kokaia Z, Lindvall O, N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci, 2001, 14: 10.
27. Bernabeu R, Sharp FR, NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J Cereb Blood Flow Metab 2000, 20: 1669.
28. Zigova T, Pencea V, Wiegand SJ, et al, Intraventricular administration of BDNF increases the number of newly generated neurons in the adultolfactory bulb. Mol Cell Neurosci, 1998, 11: 234.
29. Uchida N, Kiuchi Y, Miyamoto K, Glutamate-stimulated proliferation of rat retinal pigment epithelial cells. Eur J Pharmacol, 1998, 343: 265.
30. Zhang R, Zhang L, Zhang Z, et al, A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol, 2001, 50: 602.
31. Zhu DY, Liu SH, Sun HS, et al, Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyms. J Neurosci, 2003, 23: 223.
32. Mani S, Shen Y, Schaefer J, et al, Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons. Mol Cell.Neurosci, 2001, 17, 1754.
33. Wang XY Zhang JT, Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta. Pharmacol. Sin, 2001, 22: 1099.
34. Walton MR, Dragunow I, Is CREB a key to neuronal survival? Trends Neurosci, 2000, 23: 48.
35. Nakagawa S, Kim JE, Lee R et al, Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci, 2002, 22: 3673.
36. Liu M, Zhang JT. Effects of ginsenoside Rg1 on c-fos gene expression and cAMP levels in rat hippocampus. Acta Pharmacol Sin, 1996, 17:171
37. Mabuchi T, Kitagawa K, Kuwabara K, Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J Neurosci, 2001, 21: 9204.
38. Gould E, Beylin A, Tanapat P, Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 1999, 2: 260.
39. Shors TJ, Miesegaes G, Beylin A, Neurogenesis in the adult is involved in the formation of trace memories. Nature, 2001,410: 372.
40. Haughey NJ, Nath A, Chan SL, Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem, 2002, 83: 1509.
41. Hodges H, Veizovic T, Bray N, Conditionally immortal neuroepithelial stem cell grafts reverse age-associated memory impairments in rats. Neuroscience, 2000,101: 945.
1. Kennedy M, Firpo M, Chol K, et al, A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature, 1997, 386: 488.
2. Burt RK. Clinical utility in maximizing CD34~+ cell count in stem cell grafts. Stem cells, 1999, 17:373.
3. Wagner JE, Kernan NA, Steinbuch M, et al, Allogeneic sibling umbilical-cord-blood transplantation in chidren with malignant and non-malignant disease. The Lancet, 1995, 346: 214.
4. Pittenger MF, Mackay AM, Beck SC, Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284: 143.
5. Ferrari G, Angelis GC, Colletta M, et al, Muscle regeneration by bone marrow-derived myogenic progenitors. Science, 1998, 279: 1528.
6. Krause DS, Theise ND, Collector MI, et al, Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 2001, 105: 369.
7. Jones PH, Harper S, Watt FM. Stem cell pattering and fate in human epidermis. Cell, 1995, 80: 83.
8. Taylor G, Lehrer MS, Jensen PJ, et al, Involvement of follicullar stem cells in forming not only the follicle but also the epidermis. Cell, 2000, 120: 451.
9. Pellegrini G, Traverso CE, Franzi AT, et al, Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. The Lancet, 1997, 349, 990.
10. Schwab IR, Reyes M, Isseroff RR, Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease. Cornea, 2000, 19: 421.
11. Gage FH, Mammalian neural stem cells, Science, 2000, 287, 1433.
12. Renfranz PJ, Cunningham MG, Ronald DG Mckay, Region - specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell, 1991, 66: 731.
13. Bartlett PF, Reid HH, Bailey KA, et al, Immortalization of mouse neural precursor cells by the c-myc oncogene. Proc Natl Acad Sci USA, 1988, 85: 3255.
14. Sah DW, Ray J, Gage FH, Biopotent progenitor cell lines from the human CNS. Nat Biotechnol, 1997,15: 574.
15. Chalmers-Redman RM, Priestley T, In vitro propagation and inducible differentiation of multipotential progenitor cells from human fetal brain.Neuroscience, 1997, 76: 1121.
16. Paganoa SF, Impagnatiellob F, Girellia M, et al, Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem cells, 2000, 18: 295.
17. Roy NS, Wang S, Jiang L, In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med, 2000, 6: 271.
18. Brannen CL, Sugaya K, In vitro differentiation of multipotent human neural progenitors in serum-free medium. Neuroreport 2000, 11:1123.
19. Gottlieb DI, Huettner JE, An in vitro pathway from embryonic stem cells to neurons and glia. Cells Tissues Organs, 1999, 165:165.
20. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Embryonic stem cell lines derived from human blastocysts. Science, 1998, 282:1145.
21. Shamblott MJ, Axelman J, Wang S, Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A, 1998, 95:13726.
22. Laywell ED, Kukekov VG, Steindler DA, Multipotent neurospheres can be derived from forebrain subependymal zone and spinal cord of adult mice after protracted postmortem intervals. Exp Neurol, 1999, 156:430.
23. Palmer TD, Schwartz PH, Taupin P, et al, Cell culture. Progenitor cells from human brain after death. Nature, 2001, 411:42.
24. Sohonen JO, Peterson DA, Ray J, et al, Differentiation of adult hippocampus - derived progenitors into olfactory neurons in vivo. Nature, 1996, 383: 624.
25. Martinez-Serrano A, Lundberg CHP, Fischer W, et al, CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: complete rescue of axotomized cholinergic neurons after transplantation into the septum. J Neurosci, 1995, 15: 5668.
26. Lindvall O, Brundin P, Widner H, et al, Grafts of fetal Dopamine Neurons survive and improve motor function in Parkinson's Disease. Science, 1990, 247: 574.
27. Freeman TB, Cicchetti F, Hauser RA, et al, Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc Natl Acad Sci U S A, 2000, 97:13877.
28. Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature, 2000, 405: 951.
29. Kempermann G, Kuhn HG, Gage FH, More hippocampal neurons in adultmice living in an enriched environment. Nature, 386; 493.
30. Tanapat P, Galea Liisa AM, Gould E, et al, Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci, 1998,16: 235.
31. Craig CG, Tropepe V, Morshead CM, In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci, 1996, 16: 2649.
32. Aberg MA, Aberg ND, Hedbacker H, et al, Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci, 2000, 20:2896.
33. Haydar TF, Wang F, Schwartz ML, et al, Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci, 2000, 20:5764.
34. Bjornson CR, Rietze RL, Reynolds BA, et al, Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science, 1999, 283:534.
35. Woodbury D, Schwarz EM, Prockop DJ, et al, Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res, 2000, 61: 364.
36. Kondo T, Raff M, Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science, 2000, 289:1754.
[1] Chang SY et al. (1988) Memory facilitation induced by gynostemma, pentaphyllum and gypensode III (ginsenoside b1) in mice.Chin pharmacol Bull, 4, 358-61.
[2] Zhang JT et al. (1990) Preliminary study on antiamnestic mechanism of ginsenoside Rg1 and Rb1. Chin Med J 130, 932-8.
[3] Qiu Y et al. (1995) Protective effects of ginsenoside on the learning and memory impairment induced by transient cerebral ischemia-reperfusion in mice. Chin Pharmacol Bull 11, 299-302.
[4] Zhang DS and Zhang JT. (2000) Effects of total ginsenoside on learning and memory impairment induced by beta-amyloid peptide(25-35). Chin Pharmacol Bull 16, 422-5.
[5] Wang XY and Zhang JT. (2001) Effects of ginenoside Rg1 on learning and memory impairment induced by. Ada Pharmaceu Sin 36, 1-4.
[6] Gong YS and Zhang JT. (1999) Effect of 17 - estradiol and ginsenoside Rg1 on reactive microglia induced by. J Asian Nat Prod Res 17, 153-61.
[7] Chen J et al. Effects of 17 estradiol and total ginsenoside on the spatial learning and memory impairment of ovariectomy rats. Chin Med J 36, 522-6.
[8] Zhang DS and Zhang JT. (2000) Effect of total ginsenoside on synaptic transmission in dentate gyrus in rats. Acta Pharmaceu Sin 35, 185-8.
[9] Wang XY and Zhang JT. (2001) NO mediates ginsenoside Rg1-induced long-term potentiation in anesthetized rats. Acta Pharmacol Sin 22, 657-62.
[10] Wang XY and Zhang JT. (2001) Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action. Acta Pharmacol Sin 22, 1099-102.
[11] Zhang JT et al. (1988) Influence of ginsenoside Rb1 and Rg1 on some central neurotransmitter receptors and protein biosynthesis in mouse brain. Acta Pharmaceu Sin 23, 12-6.
[12] Liu M and Zhang JT. (1996) Influence of ginsenoside Rb1 and Rg1 on some central neurotransmitter receptors and protein biosynthesis in mouse brain. Acta Pharmacol Sin 17, 171-4.
[13] Yang Y et al. (1994) Study on the nootropic mechanism of ginsenoside Rb1 and Rg1---influence on mouse brain development. Acta Pharmaceu Sin 29, 241-5.
[14] Lian XY and Zhang JT. (1998) Effect of ginsenoside Rb1 on repeated stress-induced sexual deficiencies in male mice. Acta Pharmaceu Sin 33, 184-7.
[15] Wang XY and Zhang JT. (2002) Effect of ginsenoside Rb1 on mouse sexual function and its mechanism. Acta Pharmaceu Sin 35, 492-5.
[16] Lian XY and Zhang JT. (2001) Chronic stress and gonadectomy decrease the levels of neurotrophin-3 and brain-derived neurotrophic factor in adult mouse brain. Chin J Pharmacol Toxicol 15, 245-50.
[17] Li JQ et al. (1997) Inhibition of apoptosis by ginsenoside Rg1 in cultured cortical neurons. Chin Med J 32, 406-10.
[18] Li JQ et al. (1997) Effect of age and ginsenoside Rg1 on nitric oxide content and nitric oxide synthase activity of cerebral cortex on rats. Acta Pharmaceu Sin 32, 251-4.
[19] Liu M and Zhang JT. (2002) The immunoregulatory effects of ginsenoside Rg1 in aged rats. Acta Pharmaceu Sin 30, 818-23.
[20] Liu M and Zhang JT. (1996) Studies on the mechanisms of immunoregulatory effects of ginsenoside Rg1 in aged rats. Acta Pharmaceu Sin 31, 95-100.
[21] Gage FH. (2000) Mammalian neural stem cells. Cell 60, 585-95.
[22] Kuhn HG et al. (1996) Neurogenesis in thedentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16, 2027-33.
[23] Shors TJ et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372-6.
[24] Haughey NJ et al. (2002) Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med 1, 125-35.
[25] Shen LH and Zhang JT. (2002) Effects of ginsenoside Rg1 on neural progenitors' proliferation ability. 8~(th) Inter Symposium Ginseng, 2002, Seoul, Korean, 522.
[26] Shen LH, Zhang JT. (2003) Ginsenoside Rg1 increases ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils. Neurosci Lett, 344:1-4.
[27] Teng CM et al. (1989) Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng. Biochim Biophys Acta 990, 315-20.
[28] Kimura Y et al. (1988) Effects of various ginseng saponins on 5-hydroxytryptamine release and aggregation in human platelets. J Pharm Pharmacol 40, 838-43.
[29] Wu W et al. (1995) Effects of Panax notoginseng saponin Rg1 on cardiac electrophysiological properties and ventricular fibrillation threshold in dogs. Chin Pharmaceu Bull 16, 459-63.
[30] Zhang RB et al. (1982) Cardiac arrhythmia induced by hypothalamic stimulation in cardiac ischemic rabbits and the antiarrhythmic action of Panax ginseng. Chin Pharmaceu Bull 3, 226-30.
[31] Ikehara M et al. (1978) Effect of ginseng saponins on cholesterol metabolism. III. Effect of ginsenoside-Rb on cholesterol synthesis in rats fed on high-fat diet. Chem Pharm Bull 26, 2844-54.
[32] Kang SY et al. (1995) Dietary ginsenosides improve endothelium-dependent relaxation in the thoracic aorta of hypercholesterolemic rabbit. Gen Pharmacol 26, 483-7.
[33] Park KH et al. (2002) Possible role of ginsenoside Rb1 on regulation of rat liver triglycerides. Biol Pharm Bull 25, 457-60.
[34] Attele AS et al. (2002) Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component. Diabetes 51, 1851-8.
[35] Kang KS et al. (2000) Preventive effect of epicatechin and ginsenoside Rb(2) on the inhibition of gap junctional intercellular communication by TPA and H(2)O(2). Cancer Lett 152, 97-106.
[36] Ota T et al. (1997) G1 phase-specific suppression of the Cdk2 activity by ginsenoside Rh2 in cultured murine cells. Life Sci 60, PL39-44.
[37] Han R. (2002) Highlight on the studies of anticancer drugs derived from plants in China. Stem cells 12, 53-63.
[38] Zhang JT. (1995) The retrospection and prospect of ginseng research. Acta Pharmaceu Sin 30, 321-5.
[39] Dou DQ et al. (1999) Advances and prospects of the study on chmical constituents and pharmacological activities of Panax ginseng. J Shenyang Pharmaceu University 16, 321-5.
[40] Huang YS et al. (1989) Effect of ginsenoside Rb1 and Rg1 on lipid peroxidation of rat in vitro. Acta Academiae Medicinae Sinicae 11, 460-2.
[41] Deng HL and Zhang JT. (1991) Anti-lipid peroxydative effect of ginsenoside Rb1 and Rg1. Chin Med J 11, 395-8.
[42] Liu M and Zhang JT. Effects of ginsenoside Rb1 and Rg1 on synaptosomal free calcium level, ATPase and calmudulin in rat hippocampus. Chin Med J 108, 544-7.
[43] Jiang XY et al. (1996) Mechanism of action of ginsenoside Rb1 in decreasing intracellular Ca~(2+). Acta Pharmaceu Sin 31, 321-6.
[44] Liu M and Zhang JT. (1995) Protective effects of ginsenoside Rb1 and Rg1 in cultured hippocampal neurons. Acta Pharmaceu Sin 30, 674-8.
[45] Wang JH et al. (2001) Triterpenoid saponins from leaves and stems of Panax quinquefolium L. J Asian Nat Prod Res 3, 293-7.
[46] Yang XW et al. (2000) Ginsenoside-Rg6, a novel triterpenoid saponin from the stem-leaves of Panax ginseng C.A.Mey. Chin Chem Lett 11, 909-12.
[47] Le Tran Ouan et al. (2001) Triterpene saponins from Vietnamese Ginseng (Panax vietnamensis) and their hepatocytoprotective activities. J Nat Prod 64, 456-61.
[48] Dou DQ et al. (2001) Six new dammarane-type triterpene saponins from the leaves of Panax ginseng. Chem Pharm Bull 49, 442-6.