Curcumin Stimulates Proliferation of Embryonic Neural Progenitor Cells and Neurogenesis in the Adult Hippocampus (2008)

Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair. Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair. Neural progenitor cells (NPC) 2The abbreviations used are: NPC, neural progenitor cell; AD, Alzheimer disease; ERK, extracellular signal-regulated kinase; GFAP, glial fibrillary acidic protein; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein; NSC, neural stem cell; BrdU, bromodeoxyuridine; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMEM, Dulbecco's modified Eagle's medium; CNS, central nervous system. are the source of the neurons and glial cells that form all brain regions during embryonic development (1Alvarez-Buylla A. Garcia-Verdugo J.M. Tramontin A.D. Nat. Rev. Neurosci. 2001; 2: 287-293Crossref PubMed Scopus (856) Google Scholar). However, the adult brain retains populations of NPC in the hippocampus and subventricular region of the cerebral cortex that are capable of dividing, migrating, and differentiating into neurons (2Gould E. Nat. Rev. Neurosci. 2007; 8: 481-488Crossref PubMed Scopus (539) Google Scholar). NPC are known to respond to several types of environmental stimuli including physical exercise (3van Praag H. Christie B.R. Sejnowski T.J. Gage F.H. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 13427-13431Crossref PubMed Scopus (2317) Google Scholar, 4van Praag H. Kempermann G. Gage F.H. Nat. Neurosci. 1999; 2: 266-270Crossref PubMed Scopus (3093) Google Scholar), dietary restriction (5Lee J. Duan W. Long J.M. Ingram D.K. Mattson M.P. J. Mol. Neurosci. 2000; 15: 99-108Crossref PubMed Scopus (332) Google Scholar, 6Lee J. Duan W. Mattson M.P. J. Neurochem. 2002; 82: 1367-1375Crossref PubMed Scopus (787) Google Scholar, 7Lee J. Seroogy K.B. Mattson M.P. J. Neurochem. 2002; 80: 539-547Crossref PubMed Scopus (383) Google Scholar), and injury (8Parent J.M. Prog. Brain Res. 2007; 163: 529-817Crossref PubMed Scopus (139) Google Scholar, 9Parent J.M. Yu T.W. Leibowitz R.T. Geschwind D.H. Sloviter R.S. Lowenstein D.H. J. 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Curcumin (diferuloylmethane) is a naturally occurring phenolic yellow chemical isolated from the rhizomes of the plant Curcuma longa Linn (turmeric), and is a major component of the spice turmeric. Turmeric has traditionally been used in India for the treatment of diseases associated with injury and inflammation (13Lodha R. Bagga A. Ann. Acad. Med. Singapore. 2000; 29: 37-41PubMed Google Scholar). Because of its ability to scavenge free radicals and inhibit inflammation (14Huang M.T. Lysz T. Ferraro T. Abidi T.F. Laskin J.D. Conney A.H. Cancer Res. 1991; 51: 813-819PubMed Google Scholar, 15Ruby A.J. Kuttan G. Babu K.D. Rajasekharan K.N. Kuttan R. Cancer Lett. 1995; 94: 79-83Crossref PubMed Scopus (971) Google Scholar, 16Shishodia S. Sethi G. Aggarwal B.B. Ann. N. Y. Acad. Sci. 2005; 1056: 206-217Crossref PubMed Scopus (564) Google Scholar), curcumin has been investigated for cancer chemoprevention and tumor growth suppression. Recent findings suggest the possibility that curcumin can reduce oxidative damage and cognitive deficits associated with aging (17Chen H. Zhang Z.S. Zhang Y.L. Zhou D.Y. Anticancer Res. 1999; 19: 3675-3680PubMed Google Scholar, 18Chuang S.E. Kuo M.L. Hsu C.H. Chen C.R. Lin J.K. Lai G.M. Hsieh C.Y. Cheng A.L. Carcinogenesis. 2000; 21: 331-335Crossref PubMed Scopus (236) Google Scholar, 19Rao C.V. Rivenson A. Simi B. Reddy B.S. Ann. N. Y. Acad. Sci. 1995; 768: 201-204Crossref PubMed Scopus (57) Google Scholar). Studies of animal models have suggested that curcumin may be beneficial in neurodegenerative conditions such as AD (20Calabrese V. Butterfield D.A. Stella A.M. Ital. J. Biochem. 2003; 52: 177-181PubMed Google Scholar, 21Lim G.P. Chu T. Yang F. Beech W. Frautschy S.A. Cole G.M. J. Neurosci. 2001; 21: 8370-8377Crossref PubMed Google Scholar, 22Yang F. Lim G.P. Begum A.N. Ubeda O.J. Simmons M.R. Ambegaokar S.S. Chen P.P. Kayed R. Glabe C.G. Frautschy S.A. Cole G.M. J. Biol. Chem. 2005; 280: 5892-5901Abstract Full Text Full Text PDF PubMed Scopus (2014) Google Scholar) and focal cerebral ischemia (23Thiyagarajan M. Sharma S.S. Life Sci. 2004; 74: 969-985Crossref PubMed Scopus (376) Google Scholar). In addition, the curcumin treatment can protect hippocampal neurons against excitotoxic and traumatic injury (24Sumanont Y. Murakami Y. Tohda M. Vajragupta O. Watanabe H. Matsumoto K. Life Sci. 2006; 78: 1884-1891Crossref PubMed Scopus (82) Google Scholar, 25Wu A. Ying Z. Gomez-Pinilla F. Exp. Neurol. 2006; 197: 309-317Crossref PubMed Scopus (255) Google Scholar). In addition to the direct free radical scavenging properties of high (micromolar) concentrations of curcumin, lower concentrations can activate or inhibit one or more signal transduction pathways in cells. In tumor cells, curcumin can inhibit growth factor-mediated signaling pathways including those coupled to extracellular-regulated kinases (26Duvoix A. Blasius R. Delhalle S. Schnekenburger M. Morceau F. Henry E. Dicato M. Diederich M. Cancer Lett. 2005; 223: 181-190Crossref PubMed Scopus (749) Google Scholar, 27Suh H.W. Kang S. Kwon K.S. Mol. Cell Biochem. 2007; 298: 187-194Crossref PubMed Scopus (61) Google Scholar) and protein kinase C (28Lin J.K. Adv. Exp. Med. Biol. 2007; 595: 227-243Crossref PubMed Scopus (202) Google Scholar). On the other hand, curcumin can activate the Nrf2-ARE and p38 MAP kinase pathways in tumor cells resulting in the induction of the expression of phase 2 enzymes such as heme oxygenase-1 (29McNally S.J. Harrison E.M. Ross J.A. Garden O.J. Wigmore S.J. Int. J. Mol. Med. 2007; 19: 165-172PubMed Google Scholar). Studies of the effects of curcumin on neurons suggest that it can induce the expression of cytoprotective proteins such as heme oxygenase-1 (30Scapagnini G. Colombrita C. Amadio M. D'Agata V. Arcelli E. Sapienza M. Quattrone A. Calabrese V. Antioxid. Redox. Signal. 2006; 8: 395-403Crossref PubMed Scopus (167) Google Scholar). Emerging evidence suggests that some phytochemicals exert their health-promoting effects by activating one or more adaptive cellular stress response pathways (31Mattson M.P. Cheng A. Trends Neurosci. 2006; 29: 632-639Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). Because several of those pathways, including those involving MAP kinase, are known to regulate neurogenesis (32Menard C. Hein P. Paquin A. Savelson A. Yang X.M. Lederfein D. Barnabe-Heider F. Mir A.A. Sterneck E. Peterson A.C. Johnson P.F. Vinson C. Miller F.D. Neuron. 2002; 36: 597-610Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar), we explored the effects of curcumin on NPC in culture and in vivo. Our findings demonstrate that curcumin can enhance neurogenesis via an ERK- and p38 MAP kinase-mediated mechanism. Cell Culture Methods—C17.2 cells are multipotent NPC, which were isolated from the neonatal mouse cerebellum and immortalized (33Snyder E.Y. Deitcher D.L. Walsh C. Arnold-Aldea S. Hartwieg E.A. Cepko C.L. Cell. 1992; 68: 33-51Abstract Full Text PDF PubMed Scopus (763) Google Scholar). C17.2 NPC have been widely used as cell transplantation candidates for the treatment of several neurodegenerative disorders because they are able to integrate in the host adult brain, and differentiate into multiple stable cell phenotypes after grafting (34Niles L.P. Armstrong K.J. Rincon Castro L.M. Dao C.V. Sharma R. McMillan C.R. Doering L.C. Kirkham D.L. BMC Neurosci. 2004; 5: 41Crossref PubMed Google Scholar, 35Yang Y. Ren W. Chen F. Neuroreport. 2006; 17: 235-238Crossref PubMed Scopus (17) Google Scholar). The C17.2 NPC line (a generous gift from C. Cepko) was maintained in plastic culture flasks in Dulbecco's modified Eagle's medium (DMEM) containing and 2 in a of Cancer cell including embryonic cells mouse cells and cells were in containing and 2 in a of cells were in the conditions as the C17.2 NPC. and were from were by direct into the culture and an of was to cultures of embryonic neural stem cells, mice were on by and were The from the were into and containing were from the brain, and the was and in brain was in 2 was for and the was by of in The cells were by with a to of cells or cell The cells were in culture medium containing and growth and into or plastic culture the cell Cell proliferation was by which is on the of by the of cells into an were a of cells in the cells were with concentrations of curcumin and the medium containing curcumin was cells were with PBS, and of in was to The was for the cells were in and The by cells was in an an of and protein was by the as a and were for in a and a of of protein were by The proteins were from the an The was in a in containing and for The was in for and with for in the was with a for 2 for in was by and to protein were used for molecular The mouse against against ERK, a mouse against cells, was to the culture medium to a of for 2 and with culture medium were with or cultured cells were in in PBS, and with cells were in for in was to was by cells to and The was and the was The cells were with and for 2 in the of The cells, were with for development was a to the were and a and Curcumin mice from were maintained and conditions and and were into for and curcumin treatment and for to Curcumin was a of for was used as of neurogenesis, mice from were an of for of the mice in treatment were one after the and were after the or after curcumin mice were and with in were from the in the and to a The were in the a in Dulbecco's phosphate-buffered containing and that the hippocampal was of Neural for of brain with was to that M. Perfilieva E. Johansson U. Orwar O. Eriksson P.S. J. Neurobiol. 1999; 39: 569-578Crossref PubMed Scopus (710) Google Scholar). were with in to and was by to and The were in for and with in were a and were and with to cell of and the neuronal with was and the were with and mouse with against was Brain were with and for 2 in the of with and with were a of the and cultured cells and mice was by of with significant of were were Curcumin the of C17.2 the effect of curcumin on the proliferation of C17.2 cells in or were maintained in medium or containing increasing concentrations of curcumin and the cell proliferation was of curcumin lower of curcumin NPC proliferation, whereas high a in NPC proliferation the concentrations curcumin was the in NPC The effects of low concentrations of curcumin, during a treatment that the of curcumin was during the was to the effects of curcumin on of with a significant increase of NPC proliferation in cultures with curcumin findings that low curcumin induce the proliferation of high of curcumin are cytotoxic. the of Curcumin on was to one or more MAP kinases are activated in response to curcumin in Curcumin the of with a increase and a of p38 kinases were in NPC with However, proteins were by curcumin treatment the and p38 by curcumin were with activity to Inhibitors in the of MAP kinases is for proliferation of were with the the p38 or the to curcumin with and blocked proliferation of a for ERKs and p38 MAP kinase in the of In the significant effect on cell The of and p38 kinases were in the proliferation of in the of curcumin, indicating that and p38 kinases are involved in the proliferation of findings that and p38 kinase is involved in the of proliferation in Cell to of cancer cell have suggested that curcumin can inhibit cell proliferation, we the effects of curcumin on the proliferation of several cancer cell including cells embryonic cells mouse cells and cells were into culture containing medium in the or of curcumin and cultured for The of that was effect of curcumin on of the cancer cell indicating the mitogenic of curcumin were that curcumin activate signaling in the cancer cell Curcumin the of Neural via the MAP effect of curcumin was investigated on neural stem cells from embryonic mouse cerebral were with or curcumin for was after to The effect of curcumin on was the Because the and p38 MAP kinase pathways the effects of curcumin in C17.2 we the pathways proliferation of embryonic that curcumin activated and p38 kinases, whereas was by curcumin treatment The and the p38 effectively blocked the proliferation of embryonic mouse as as proliferation C17.2 NPC, the a effect on the proliferation of proliferation, and blocked the proliferation of embryonic mouse that and p38 kinases are more for cell proliferation in and are involved in the of and p38 MAP kinases the effects of curcumin on embryonic neural stem cells. cell from cultures that been for 2 with curcumin were to with against or of ERK, JNK, and were used to protein The is of in and p38 MAP kinase proliferation of embryonic mouse with the MAP kinase for were with or curcumin for proliferation was by are the and S.E. with the for with the for cultures with curcumin Curcumin the of in the of the in the possible effects of curcumin on adult of the hippocampus, we curcumin or was a of for on we that of in a of curcumin in the of F. Lim G.P. Begum A.N. Ubeda O.J. Simmons M.R. Ambegaokar S.S. Chen P.P. Kayed R. Glabe C.G. Frautschy S.A. Cole G.M. J. Biol. Chem. 2005; 280: 5892-5901Abstract Full Text Full Text PDF PubMed Scopus (2014) Google Scholar). into of the we that a of curcumin in a in the the newly generated cells, of were for on the of curcumin were or after the The cells with were by the the of cells in the dentate gyrus were in mice with mice A and the were more cells in the dentate gyrus of mice in the curcumin with the A and the the cells were the cell and their were and of neurons. Curcumin the phenotypes of the newly generated cells, we on the against the protein in with the after the of cells was in the of dentate gyrus and was with the after cells were the dentate all cells that were the cell were that of the cells that in the cell into neurons with and was that the of newly generated cells dentate gyrus after were with that the of curcumin hippocampal neurogenesis in adult we that more cells were in the subventricular region of mice after the that curcumin the proliferation of neural stem cells in dentate gyrus but in the subventricular region of the cerebral cortex have and effects of concentrations of curcumin in cultured tumor cell as as cells (17Chen H. Zhang Z.S. Zhang Y.L. Zhou D.Y. Anticancer Res. 1999; 19: 3675-3680PubMed Google Scholar, 18Chuang S.E. Kuo M.L. Hsu C.H. Chen C.R. Lin J.K. Lai G.M. Hsieh C.Y. Cheng A.L. Carcinogenesis. 2000; 21: 331-335Crossref PubMed Scopus (236) Google Scholar, 19Rao C.V. Rivenson A. Simi B. Reddy B.S. Ann. N. Y. 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Med. 2007; 19: 165-172PubMed Google Scholar). that a of curcumin p38 However, the lower of curcumin is to and activate the stress p38 in cancer cells in the In of findings that curcumin the proliferation of types of cancer cells A. Aggarwal B.B. Biochem. PubMed Scopus Google Scholar), findings suggest that the effects of curcumin on cell proliferation and MAP kinase signaling in neural stem cells are cell The for effect of curcumin on neural stem cells and cancer cells to be The molecular by which curcumin and p38 MAP kinases is unknown. possibility is that curcumin with the kinases or kinases or of the MAP has been is for direct of such as with signal transduction suggest that curcumin can activate the response by with and the E. M. P. E. R. J. R. Biochem. J. 2003; PubMed Scopus Google Scholar). the of and p38 MAP kinases may an adaptive response of the cells to stress by is evidence that high (micromolar) concentrations of curcumin can induce oxidative and that may its ability to in cancer cells S. E. C. Med. 2007; 181-190Crossref PubMed Scopus Google Scholar). of curcumin may induce a adaptive stress response that the of and p38 MAP kinases resulting in proliferation and survival of neural stem cells. The is with the for the beneficial phytochemicals on neurons (31Mattson M.P. Cheng A. Trends Neurosci. 2006; 29: 632-639Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). was reported that curcumin treatment can hippocampal neurogenesis in Y. B. Brain Res. 2007; PubMed Scopus Google Scholar). However, in the study, high and of curcumin were and the effects of curcumin were on the of hippocampal neurogenesis by chronic in of curcumin were on the ability of high of curcumin to protect neurons against types of stress A. 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