Korean J Physiol Pharmacol.  2012 Feb;16(1):1-9. 10.4196/kjpp.2012.16.1.1.

Stem Cells in Drug Screening for Neurodegenerative Disease

• Kim HJ
• Jin CY

• KMID: 2285433
• DOI: http://doi.org/10.4196/kjpp.2012.16.1.1

Abstract

Because the average human life span has recently increased, the number of patients who are diagnosed with neurodegenerative diseases has escalated. Recent advances in stem cell research have given us access to unlimited numbers of multi-potent or pluripotent cells for screening for new drugs for neurodegenerative diseases. Neural stem cells (NSCs) are a good model with which to screen effective drugs that increase neurogenesis. Recent technologies for human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) can provide human cells that harbour specific neurodegenerative disease. This article discusses the use of NSCs, ESCs and iPSCs for neurodegenerative drug screening and toxicity evaluation. In addition, we introduce drugs or natural products that are recently identified to affect the stem cell fate to generate neurons or glia.

Keyword

Stem cells; Neurodegeneration; Drug screening; IPS; ES cells

MeSH Terms

Biological Agents
Drug Evaluation, Preclinical
Embryonic Stem Cells
Humans
Induced Pluripotent Stem Cells
Mass Screening
Neural Stem Cells
Neurodegenerative Diseases
Neurogenesis
Neuroglia
Neurons
Stem Cell Research
Stem Cells
Biological Agents

Figure

• 

  Fig. 1 High-throughput screening for the development of new drugs that are effective for the treatment of neurodegenerative diseases. NSC can be derived from adult cells, fetus cells, ESCs or iPSCs. After NSC plating, chemical or natural product libraries are treated. The effect of each drugs are detected by immunocytochemistry using cell type specific antibodies. If fluorescence conjugated secondary antibodies are used, cells can be visualized by fluorescence microscopy and the numbers of detected/differentiated cells are counted. If HRP conjugated secondary antibodies are used, cells can be treated with substrates and lysed to be measured by microplate reader. Once the chemicals or natural products that are effective are found, and structural activity relationship studies, animal studies and toxicity evaluations are done, promising agents can go on to clinical trials and may further be developed as new drugs.

Reference

1. Kim HJ. Stem cell potential in Parkinson's disease and molecular factors for the generation of dopamine neurons. Biochim Biophys Acta. 2011. 1812:1–11.

2. Jones JM, Thomson JA. Human embryonic stem cell technology. Semin Reprod Med. 2000. 18:219–223.

3. Studer L, Tabar V, McKay RD. Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci. 1998. 1:290–295.

4. Sánchez-Pernaute R, Studer L, Bankiewicz KS, Major EO, McKay RD. In vitro generation and transplantation of precursor-derived human dopamine neurons. J Neurosci Res. 2001. 65:284–288.

5. Levy YS, Stroomza M, Melamed E, Offen D. Embryonic and adult stem cells as a source for cell therapy in Parkinson's disease. J Mol Neurosci. 2004. 24:353–386.

6. Chen LW, Kuang F, Wei LC, Ding YX, Yung KK, Chan YS. Potential application of induced pluripotent stem cells in cell replacement therapy for Parkinson's disease. CNS Neurol Disord Drug Targets. 2011. 10:449–458.

7. Lindvall O, Kokaia Z. Stem cell therapy for human brain disorders. Kidney Int. 2005. 68:1937–1939.

8. Germain N, Banda E, Grabel L. Embryonic stem cell neurogenesis and neural specification. J Cell Biochem. 2010. 111:535–542.

9. Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci. 1995. 108:3181–3188.

10. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, Livne E, Binah O, Itskovitz-Eldor J, Gepstein L. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001. 108:407–414.

11. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002. 91:501–508.

12. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003. 107:2733–2740.

13. Noguchi H. Production of pancreatic beta-cells from stem cells. Curr Diabetes Rev. 2010. 6:184–190.

14. Shi Y. Generation of functional insulin-producing cells from human embryonic stem cells in vitro. Methods Mol Biol. 2010. 636:79–85.

15. Chen C, Zhang Y, Sheng X, Huang C, Zang YQ. Differentiation of embryonic stem cells towards pancreatic progenitor cells and their transplantation into streptozotocin-induced diabetic mice. Cell Biol Int. 2008. 32:456–461.

16. Yamamoto H, Quinn G, Asari A, Yamanokuchi H, Teratani T, Terada M, Ochiya T. Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology. 2003. 37:983–993.

17. Teratani T, Yamamoto H, Aoyagi K, Sasaki H, Asari A, Quinn G, Sasaki H, Terada M, Ochiya T. Direct hepatic fate specification from mouse embryonic stem cells. Hepatology. 2005. 41:836–846.

18. Van Haute L, De Block G, Liebaers I, Sermon K, De Rycke M. Generation of lung epithelial-like tissue from human embryonic stem cells. Respir Res. 2009. 10:105.

19. Wang D, Haviland DL, Burns AR, Zsigmond E, Wetsel RA. A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci USA. 2007. 104:4449–4454.

20. Yamamoto M, Tachibana T, Hashimoto H, Ishiwata I, Ishikawa H. The differentiation of early embryonic stem cells into adipocytes-like cells. Hum Cell. 2003. 16:117–122.

21. Kim HJ, Rosenfeld MG. Epigenetic control of stem cell fate to neurons and glia. Arch Pharm Res. 2010. 33:1467–1473.

22. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998. 282:1145–1147.

23. Suemori H. Establishment and therapeutic use of human embryonic stem cell lines. Hum Cell. 2006. 19:65–70.

24. Gepstein L. Derivation and potential applications of human embryonic stem cells. Circ Res. 2002. 91:866–876.

25. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000. 18:399–404.

26. Pera MF, Reubinoff B, Trounson A. Human embryonic stem cells. J Cell Sci. 2000. 113:5–10.

27. Lim JM, Lee M, Lee EJ, Gong SP, Lee ST. Stem cell engineering: limitation, alternatives, and insight. Ann NY Acad Sci. 2011. 1229:89–98.

28. Hyun I. The bioethics of stem cell research and therapy. J Clin Invest. 2010. 120:71–75.

29. Tasso R, Pennesi G. When stem cells meet immunoregulation. Int Immunopharmacol. 2009. 9:596–598.

30. Cabrera CM, Cobo F, Nieto A, Concha A. Strategies for preventing immunologic rejection of transplanted human embryonic stem cells. Cytotherapy. 2006. 8:517–518.

31. Usas A, Mačiulaitis J, Mačiulaitis R, Jakubonienė N, Milašius A, Huard J. Skeletal muscle-derived stem cells: Implications for cell-mediated therapies. Medicina (Kaunas). 2011. 47:469–479.

32. Frati C, Savi M, Graiani G, Lagrasta C, Cavalli S, Prezioso L, Rossetti P, Mangiaracina C, Ferraro F, Madeddu D, Musso E, Stilli D, Rossini A, Falco A, Angelis AD, Rossi F, Urbanek K, Leri A, Kajstura J, Anversa P, Quaini E, Quaini F. Resident cardiac stem cells. Curr Pharm Des. 2011. 17:3252–3257.

33. Fuh E, Brinton TJ. Bone marrow stem cells for the treatment of ischemic heart disease: a clinical trial review. J Cardiovasc Transl Res. 2009. 2:202–218.

34. Chugh AR, Zuba-Surma EK, Dawn B. Bone marrow-derived mesenchymal stems cells and cardiac repair. Minerva Cardioangiol. 2009. 57:185–202.

35. Woo DH, Kim SK, Lim HJ, Heo J, Park HS, Kang GY, Kim SE, You HJ, Hoeppner DJ, Kim Y, Kwon H, Choi TH, Lee JH, Hong SH, Song KW, Ahn EK, Chenoweth JG, Tesar PJ, McKay RD, Kim JH. Direct and indirect contribution of human embryonic stem cellderived hepatocytelike cells to liver repair in mice. Gastroenterology. 2000. http://dx.doi.org/10.1053/j.gastro.2011.11.030.

36. Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, Mendel G, Wauthier E, Barbier C, Alvaro D, Reid LM. Human hepatic stem cell and maturational liver lineage biology. Hepatology. 2011. 53:1035–1045.

37. Grisar JC, Haddad F, Gomari FA, Wu JC. Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent. Biomark Med. 2011. 5:731–744.

38. Gage FH. Mammalian neural stem cells. Science. 2000. 287:1433–1438.

39. Kim HJ, McMillan E, Han F, Svendsen CN. Regionally specified human neural progenitor cells derived from the mesencephalon and forebrain undergo increased neurogenesis following overexpression of ASCL1. Stem Cells. 2009. 27:390–398.

40. Kim HJ, Sugimori M, Nakafuku M, Svendsen CN. Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. Exp Neurol. 2007. 203:394–405.

41. Holowacz T, Huelsken J, Dufort D, van der Kooy D. Neural stem cells are increased after loss of β-catenin, but neural progenitors undergo cell death. Eur J Neurosci. 2011. 33:1366–1375.

42. Hsu YC, Lee DC, Chiu IM. Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant. 2007. 16:133–150.

43. Jepsen K, Solum D, Zhou T, McEvilly RJ, Kim HJ, Glass CK, Hermanson O, Rosenfeld MG. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature. 2007. 450:415–419.

44. Abematsu M, Smith I, Nakashima K. Mechanisms of neural stem cell fate determination: extracellular cues and intracellular programs. Curr Stem Cell Res Ther. 2006. 1:267–277.

45. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006. 126:663–676.

46. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007. 131:861–872.

47. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature. 2008. 454:646–650.

48. Liao J, Wu Z, Wang Y, Cheng L, Cui C, Gao Y, Chen T, Rao L, Chen S, Jia N, Dai H, Xin S, Kang J, Pei G, Xiao L. Enhanced efficiency of generating induced pluripotent stem (iPS) cells from human somatic cells by a combination of six transcription factors. Cell Res. 2008. 18:600–603.

49. Durnaoglu S, Genc S, Genc K. Patient-specific pluripotent stem cells in neurological diseases. Stem Cells Int. 2011. 2011:212487.

50. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009. 136:964–977.

51. Saporta MA, Grskovic M, Dimos JT. Induced pluripotent stem cells in the study of neurological diseases. Stem Cell Res Ther. 2011. 2:37.

52. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008. 321:1218–1221.

53. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2009. 457:277–280.

54. Ebert AD, Svendsen CN. Human stem cells and drug screening: opportunities and challenges. Nat Rev Drug Discov. 2010. 9:367–372.

55. Lian Q, Chow Y, Esteban MA, Pei D, Tse HF. Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases. Thromb Haemost. 2010. 104:39–44.

56. Maury Y, Gauthier M, Peschanski M, Martinat C. Human pluripotent stem cells for disease modelling and drug screening. Bioessays. 2012. 34:61–71.

57. Rowntree RK, McNeish JD. Induced pluripotent stem cells: opportunities as research and development tools in 21st century drug discovery. Regen Med. 2010. 5:557–568.

58. Trosko JE, Chang CC. Factors to consider in the use of stem cells for pharmaceutic drug development and for chemical safety assessment. Toxicology. 2010. 270:18–34.

59. Redmond DE Jr, Sladek JR, Spencer DD. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001. 345:146–147.

60. Dunnett SB. Transplantation of embryonic dopamine neurons: what we know from rats. J Neurol. 1991. 238:65–74.

61. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001. 344:710–719.

62. Olanow CW, Freeman T, Kordower J. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001. 345:146.

63. Visnyei K, Onodera H, Damoiseaux R, Saigusa K, Petrosyan S, De Vries D, Ferrari D, Saxe J, Panosyan EH, Masterman-Smith M, Mottahedeh J, Bradley KA, Huang J, Sabatti C, Nakano I, Kornblum HI. A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells. Mol Cancer Ther. 2011. 10:1818–1828.

64. Inamdar AA, Moore JC, Cohen RI, Bennett JW. A model to evaluate the cytotoxicity of the fungal volatile organic compound 1-octen-3-ol in human embryonic stem cells. Mycopathologia. 2012. 173:13–20.

65. Takahashi J, Palmer TD, Gage FH. Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adultderived neural stem cell cultures. J Neurobiol. 1999. 38:65–81.

66. Rohwedel J, Guan K, Wobus AM. Induction of cellular differentiation by retinoic acid in vitro. Cells Tissues Organs. 1999. 165:190–202.

67. Kim HJ, Leeds P, Chuang DM. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem. 2009. 110:1226–1240.

68. Yoo DY, Kim W, Nam SM, Kim DW, Chung JY, Choi SY, Yoon YS, Won MH, Hwang IK. Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus. Neurochem Res. 2011. 36:1850–1857.

69. Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci USA. 2004. 101:16659–16664.

70. Lennington JB, Yang Z, Conover JC. Neural stem cells and the regulation of adult neurogenesis. Reprod Biol Endocrinol. 2003. 1:99.

71. 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. 16:2027–2033.

72. García-Verdugo JM, Doetsch F, Wichterle H, Lim DA, Alvarez-Buylla A. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol. 1998. 36:234–248.

73. Pencea V, Bingaman KD, Freedman LJ, Luskin MB. Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain. Exp Neurol. 2001. 172:1–16.

74. Rishton GM. Small molecules that promote neurogenesis in vitro. Recent Pat CNS Drug Discov. 2008. 3:200–208.

75. Taupin P. Neurogenic drugs and compounds. Recent Pat CNS Drug Discov. 2010. 5:253–257.

76. Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 2003. 28:1562–1571.

77. Chadwick W, Mitchell N, Caroll J, Zhou Y, Park SS, Wang L, Becker KG, Zhang Y, Lehrmann E, Wood WH 3rd, Martin B, Maudsley S. Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity. PLoS One. 2011. 6:e21660.

78. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000. 20:9104–9110.

79. Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, Arango V. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009. 34:2376–2389.

80. Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, Price J, Pariante CM. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011. 16:738–750.

81. Marcussen AB, Flagstad P, Kristjansen PE, Johansen FF, Englund U. Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats. Acta Neurol Scand. 2008. 117:94–100.

82. Rozzini L, Chilovi BV, Conti M, Bertoletti E, Zanetti M, Trabucchi M, Padovani A. Efficacy of SSRIs on cognition of Alzheimer's disease patients treated with cholinesterase inhibitors. Int Psychogeriatr. 2010. 22:114–119.

83. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci USA. 2006. 103:8233–8238.

84. Ohira K, Miyakawa T. Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice. Mol Brain. 2011. 4:10.

85. Peng ZW, Xue YY, Wang HN, Wang HH, Xue F, Kuang F, Wang BR, Chen YC, Zhang LY, Tan QR. Sertraline promotes hippocampus-derived neural stem cells differentiating into neurons but not glia and attenuates LPS-induced cellular damage. Prog Neuropsychopharmacol Biol Psychiatry. 2012. 36:183–188.

86. Hellweg R, Ziegenhorn A, Heuser I, Deuschle M. Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Pharmacopsychiatry. 2008. 41:66–71.

87. Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Toda H, Song N, Kitaichi Y, Inoue T, Koyama T. Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells. Prog Neuropsychopharmacol Biol Psychiatry. 2011. 35:111–117.

88. Hanson ND, Nemeroff CB, Owens MJ. Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther. 2011. 337:180–186.

89. Fiorentini A, Rosi MC, Grossi C, Luccarini I, Casamenti F. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS One. 2010. 5:e14382.

90. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004. 24:6590–6599.

91. Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA. The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem. 2004. 91:238–251.

92. Jung GA, Yoon JY, Moon BS, Yang DH, Kim HY, Lee SH, Bryja V, Arenas E, Choi KY. Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol. 2008. 9:66.

93. Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH. Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and upregulation of Bcl-XL. J Biomed Sci. 2011. 18:48.

94. Wurdak H, Zhu S, Min KH, Aimone L, Lairson LL, Watson J, Chopiuk G, Demas J, Charette B, Halder R, Weerapana E, Cravatt BF, Cline HT, Peters EC, Zhang J, Walker JR, Wu C, Chang J, Tuntland T, Cho CY, Schultz PG. A small molecule accelerates neuronal differentiation in the adult rat. Proc Natl Acad Sci USA. 2010. 107:16542–16547.

95. Chang DJ, Jeong MY, Song J, Jin CY, Suh YG, Kim HJ, Min KH. Discovery of small molecules that enhance astrocyte differentiation in rat fetal neural stem cells. Bioorg Med Chem Lett. 2011. 21:7050–7053.

96. Saxe JP, Wu H, Kelly TK, Phelps ME, Sun YE, Kornblum HI, Huang J. A phenotypic small-molecule screen identifies an orphan ligand-receptor pair that regulates neural stem cell differentiation. Chem Biol. 2007. 14:1019–1030.

97. Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL. Discovery of a proneurogenic, neuroprotective chemical. Cell. 2010. 142:39–51.

98. Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, Mahmood A, Chen J, Li Y, Chopp M. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma. 2007. 24:1132–1146.

99. Lu D, Goussev A, Chen J, Pannu P, Li Y, Mahmood A, Chopp M. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma. 2004. 21:21–32.

100. Kong PJ, Kim YM, Lee HJ, Kim SS, Yoo ES, Chun W. Neuroprotective effects of methanol extracts of Jeju native plants on hydrogen peroxide-induced cytotoxicity in SH-SY5Y human neuroblastoma Cells. Korean J Physiol Pharmacol. 2007. 11:171–174.

101. Kwon MS, Lee JK, Park SH, Sim YB, Jung JS, Won MH, Kim SM, Suh HW. Neuroprotective effect of visnagin on kainic acid-induced neuronal cell death in the mice hippocampus. Korean J Physiol Pharmacol. 2010. 14:257–263.

102. Chae HS, Kang YK, Shin YK, Lee HJ, Yu JI, Lee KG, Yeo JH, Kim YS, Sohn DS, Kim KY, Lee WB, Lee SH, Kim SS. The role of BF-7 on neuroprotection and enhancement of cognitive function. Korean J Physiol Pharmacol. 2004. 8:173–179.

103. Park HJ, Shim HS, Kim H, Kim KS, Lee H, Hahm DH, Shim I. Effects of glycyrrhizae radix on repeated restraint stressinduced neurochemical and behavioral responses. Korean J Physiol Pharmacol. 2010. 14:371–376.

104. Weng MS, Liao CH, Yu SY, Lin JK. Garcinol promotes neurogenesis in rat cortical progenitor cells through the duration of extracellular signal-regulated kinase signaling. J Agric Food Chem. 2011. 59:1031–1040.

105. Liu JW, Tian SJ, de Barry J, Luu B. Panaxadiol glycosides that induce neuronal differentiation in neurosphere stem cells. J Nat Prod. 2007. 70:1329–1334.

106. de Sampaio e Spohr TC, Stipursky J, Sasaki AC, Barbosa PR, Martins V, Benjamim CF, Roque NF, Costa SL, Gomes FC. Effects of the flavonoid casticin from Brazilian Croton betulaster in cerebral cortical progenitors in vitro: direct and indirect action through astrocytes. J Neurosci Res. 2010. 88:530–541.

107. Cho JY, Kon PJ, Chun W, Moon YO, Park YT, Lim SY, Kim SS. Curcumin attenuates glial cell activation but cannot suppress hippocampal CA3 neuronal cell death in i.c.v. kanic acid injection model. Korean J Physiol Pharmacol. 2003. 7:307–310.

108. Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP, Lee J. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem. 2008. 283:14497–14505.

109. Yoo DY, Kim W, Yoo KY, Lee CH, Choi JH, Kang IJ, Yoon YS, Kim DW, Won MH, Hwang IK. Effects of Nelumbo nucifera rhizome extract on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia animal model. Phytother Res. 2011. 25:809–815.

110. Yang WM, Shim KJ, Choi MJ, Park SY, Choi BJ, Chang MS, Park SK. Novel effects of Nelumbo nucifera rhizome extract on memory and neurogenesis in the dentate gyrus of the rat hippocampus. Neurosci Lett. 2008. 443:104–107.

111. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ. Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008. 451:141–146.

112. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007. 318:1917–1920.

113. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ. Disease-specific induced pluripotent stem cells. Cell. 2008. 134:877–886.

114. Soldner F, Laganire J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK, Vu BJ, Meng X, Urnov FD, Rebar EJ, Gregory PD, Zhang HS, Jaenisch R. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell. 2011. 146:318–331.

115. Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD, Dubova I, Goebl A, Plongthongkum N, Fung HL, Zhang K, Loring JF, Laurent LC, Izpisua Belmonte JC. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell. 2011. 8:688–694.