Abstract
Ginkgo biloba extract (GBE) has been widely used for treatment of neural damage and disorders. Neural stem cells (NSCs) hold promise as a treatment of hearing loss caused by neural damage. However, the biological functions of GBE in modulating NSC behaviors in the cochlea are still largely elusive. In this study, we sought to explore the effects of GBE on the differentiation and performance of NSCs from mouse cochlea. Our data showed that GBE treatment promotes cell survival and NSC proliferation. In addition, GBE treatment also increases NSC differentiation to neurons and enhances the performance of mature neural networks evident by the increased frequency of calcium oscillation. Moreover, neurite outgrowth is also dramatically increased upon GBE treatment. Overall, our study demonstrates the positive regulatory role of GBE in NSC proliferation and differentiation into functional neurons in vitro, supporting the potential therapeutic use of GBE in hearing loss recovery.
Similar content being viewed by others
References
Chaddah R, Arntfield M, Runciman S, Clarke L, van der Kooy D (2012) Clonal neural stem cells from human embryonic stem cell colonies. J Neurosci 32(23):7771–7781
Chan WH (2006) Ginkgolide B induces apoptosis and developmental injury in mouse embryonic stem cells and blastocysts. Hum Reprod 21(11):2985–2995. doi:10.1093/humrep/del255
Chen W, Jongkamonwiwat N, Abbas L, Eshtan SJ, Johnson SL, Kuhn S, Milo M, Thurlow JK, Andrews PW, Marcotti W, Moore HD, Rivolta MN (2012) Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 490(7419):278–282
Coleman B, Fallon JB, Pettingill LN, de Silva MG, Shepherd RK (2007) Auditory hair cell explant co-cultures promote the differentiation of stem cells into bipolar neurons. Exp Cell Res 313(2):232–243
Diensthuber M, Oshima K, Heller S (2009) Stem/progenitor cells derived from the cochlear sensory epithelium give rise to spheres with distinct morphologies and features. J Assoc Res Otolaryngol 10(2):173–190. doi:10.1007/s10162-009-0161-3
EGb 761: Ginkgo biloba extract, Ginkor (2003) Drugs in R&D 4(3):188–193
Fehske CJ, Leuner K, Muller WE (2009) Ginkgo biloba extract (EGb 761) influences monoaminergic neurotransmission via inhibition of NE uptake, but not MAO activity after chronic treatment. Pharmacol Res 60(1):68–73
Gage FH (2000) Mammalian neural stem cells. Science (New York, NY) 287(5457):1433–1438
Hofferberth B (1994) The efficacy of EGb 7611 in patients with senile dementia of the Alzheimer type, a double-blind, placebocontrolled study on different levels of investigation. Hum Psychopharmacol Clin Exp 9:215–222
Hu Z, Ulfendahl M, Olivius NP (2005) NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear. Neurobiol Dis 18(1):184–192
Itil TM, Eralp E, Tsambis E, Itil KZ, Stein U (1996) Central nervous system effects of Ginkgo biloba, a plant extract. Am J Ther 3(1):63–73
Kampkotter A, Pielarski T, Rohrig R, Timpel C, Chovolou Y, Watjen W, Kahl R (2007) The Ginkgo biloba extract EGb 761 reduces stress sensitivity, ROS accumulation and expression of catalase and glutathione S-transferase 4 in Caenorhabditis elegans. Pharmacol Res 55(2):139–147
Kang X, Chen J, Xu Z, Li H, Wang B (2007) Protective effects of Ginkgo biloba extract on paraquat-induced apoptosis of PC12 cells. Toxicol In Vitro 21(6):1003–1009. doi:10.1016/j.tiv.2007.02.004
Kim KS, Rhee KH, Yoon JH, Lee JG, Lee JH, Yoo JB (2005) Ginkgo biloba extract (EGb 761) induces apoptosis by the activation of caspase-3 in oral cavity cancer cells. Oral Oncol 41(4):383–389. doi:10.1016/j.oraloncology.2004.09.013
Kotakadi VS, Jin Y, Hofseth AB, Ying L, Cui X, Volate S, Chumanevich A, Wood PA, Price RL, McNeal A, Singh UP, Singh NP, Nagarkatti M, Nagarkatti PS, Matesic LE, Auclair K, Wargovich MJ, Hofseth LJ (2008) Ginkgo biloba extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis. Carcinogenesis 29(9):1799–1806. doi:10.1093/carcin/bgn143
Li S, Tang D, Xue Z, Zhang Z, Sun X, Liu Y, Dong H, Yin X, Zhang Z (2011) Biphasic effect of EGb 761 on simulated ischemia-induced rat BMSC survival in vitro and in vivo. Life Sci 88(19–20):853–863. doi:10.1016/j.lfs.2011.03.002
Matsumoto M, Nakagawa T, Higashi T, Kim TS, Kojima K, Kita T, Sakamoto T, Ito J (2005) Innervation of stem cell-derived neurons into auditory epithelia of mice. NeuroReport 16(8):787–790
Meiri KF, Pfenninger KH, Willard MB (1986) Growth-associated protein, GAP-43, a polypeptide that is induced when neurons extend axons, is a component of growth cones and corresponds to pp46, a major polypeptide of a subcellular fraction enriched in growth cones. Proc Natl Acad Sci USA 83(10):3537–3541
Morgenstern C, Biermann E (2002) The efficacy of Ginkgo special extract EGb 761 in patients with tinnitus. Int J Clin Pharmacol Ther 40(5):188–197
Nada SE, Shah ZA (2012) Preconditioning with Ginkgo biloba (EGb 761(R)) provides neuroprotection through HO1 and CRMP2. Neurobiol Dis 46(1):180–189. doi:10.1016/j.nbd.2012.01.006
Nada SE, Tulsulkar J, Shah ZA (2014) Heme oxygenase 1-mediated neurogenesis is enhanced by Ginkgo biloba (EGb 761(R)) after permanent ischemic stroke in mice. Mol Neurobiol 49(2):945–956. doi:10.1007/s12035-013-8572-x
Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110(4):429–441
Parker MA (2011) Biotechnology in the treatment of sensorineural hearing loss: foundations and future of hair cell regeneration. J Speech Lang Hear Res 54(6):1709–1731
Parker MA, Corliss DA, Gray B, Anderson JK, Bobbin RP, Snyder EY, Cotanche DA (2007) Neural stem cells injected into the sound-damaged cochlea migrate throughout the cochlea and express markers of hair cells, supporting cells, and spiral ganglion cells. Hear Res 232(1–2):29–43
Ramassamy C, Christen Y, Clostre F, Costentin J (1992) The Ginkgo biloba extract, EGb 761, increases synaptosomal uptake of 5-hydroxytryptamine: in vitro and ex vivo studies. J Pharm Pharmacol 44(11):943–945
Rietze RL, Valcanis H, Brooker GF, Thomas T, Voss AK, Bartlett PF (2001) Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412(6848):736–739
Rojas P, Montes S, Serrano-Garcia N, Rojas-Castaneda J (2009) Effect of EGb 761 supplementation on the content of copper in mouse brain in an animal model of Parkinson’s disease. Nutrition 25(4):482–485. doi:10.1016/j.nut.2008.10.013
Russo I, Barlati S, Bosetti F (2011) Effects of neuroinflammation on the regenerative capacity of brain stem cells. J Neurochem 116(6):947–956
Saleem S, Zhuang H, Biswal S, Christen Y, Dore S (2008) Ginkgo biloba extract neuroprotective action is dependent on heme oxygenase 1 in ischemic reperfusion brain injury. Stroke 39(12):3389–3396. doi:10.1161/STROKEAHA.108.523480
Semlitsch HV, Anderer P, Saletu B, Binder GA, Decker KA (1995) Cognitive psychophysiology in nootropic drug research: effects of Ginkgo biloba on event-related potentials (P300) in age-associated memory impairment. Pharmacopsychiatry 28(4):134–142
Shi C, Zhao L, Zhu B, Li Q, Yew DT, Yao Z, Xu J (2009) Dosage effects of EGb 761 on hydrogen peroxide-induced cell death in SH-SY5Y cells. Chem Biol Interact 180(3):389–397. doi:10.1016/j.cbi.2009.04.008
Tunali-Akbay T, Sener G, Salvarli H, Sehirli O, Yarat A (2007) Protective effects of Ginkgo biloba extract against mercury(II)-induced cardiovascular oxidative damage in rats. Phytother Res 21(1):26–31
Urbanska M, Blazejczyk M, Jaworski J (2008) Molecular basis of dendritic arborization. Acta Neurobiol Exp 68(2):264–288
Wei D, Levic S, Nie L, Gao WQ, Petit C, Jones EG, Yamoah EN (2008) Cells of adult brain germinal zone have properties akin to hair cells and can be used to replace inner ear sensory cells after damage. Proc Natl Acad Sci USA 105(52):21000–21005
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26(50):13102–13113
Yuan Y, Wang Y, Chi F (2014) Reinnervation of hair cells by neural stem cell-derived neurons. Chin Med J 127(16):2972–2976
Zhang Y, Chen AY, Li M, Chen C, Yao Q (2008) Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. J Surg Res 148(1):17–23
Zong L, Chen K, Zhou W, Jiang D, Sun L, Zhang X, Jiang H (2014) Inner ear stem cells derived feeder layer promote directional differentiation of amniotic fluid stem cells into functional neurons. Hear Res 316:57–64
Acknowledgments
This work was funded by the National Natural Science Foundation of China, General Program (no. 81371093).
Conflict of interest
Congpin Wang and Zhao Han declare that they have no conflict of interest.
Ethical approval
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, C., Han, Z. Ginkgo Biloba Extract Enhances Differentiation and Performance of Neural Stem Cells in Mouse Cochlea. Cell Mol Neurobiol 35, 861–869 (2015). https://doi.org/10.1007/s10571-015-0180-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-015-0180-z