(−)-Epigallocatechin-3‑gallate (EGCG), the predominant constituent of green tea, has been demonstrated to be neuroprotective against acute ischemic stroke. However, the long-term actions of EGCG on neurogenesis and functional recovery after ischemic stroke have not been identified. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 28 days. Neural progenitor cells (NPCs) were isolated from ipsilateral subventricular zone (SVZ) at 14 days post-ischemia (dpi). The effects of EGCG on the proliferation and differentiation of NPCs were examined in vivo and in vitro. Behavioral assessments were made 3 days before MCAO and at 28 dpi. SVZ NPCs were stimulated with lipopolysaccharide (LPS) in vitro to mimic the inflammatory response after ischemic stroke. We found that 14 days treatment with EGCG significantly increased the proliferation of SVZ NPCs and the migration of SVZ neuroblasts, as well as functional recovery, perhaps through M2 phenotype induction in microglia. LPS stimulation promoted the neuronal differentiation in cultured NPCs from the ischemic SVZ. EGCG treatment (20 or 40 μM) further significantly increased the neuronal differentiation of LPS-stimulated SVZ NPCs. After screening for multiple signaling pathways, the AKT signaling pathway was found to be involved in EGCG-mediated proliferation and neuronal differentiation of NPCs in vitro. Taken together, our results reveal a previously uncharacterized role of EGCG in the augment of proliferation and neuronal differentiation of SVZ NPCs and subsequent spontaneous recovery after ischemic stroke. Thus, the beneficial effects of EGCG on neurogenesis and stroke recovery should be considered in developing therapeutic approaches.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES et al (2014) Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129:e28–e292
Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, Bhatt DL, Grau-Sepulveda MV et al (2013) Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes 6:543–549
Suzuki Y, Miyoshi N, Isemura M (2012) Health-promoting effects of green tea. Proc Jpn Acad Ser B Phys Biol Sci 88:88–101
Graham HN (1992) Green tea composition, consumption, and polyphenol chemistry. Prev Med 21:334–350
Singh BN, Shankar S, Srivastava RK (2011) Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 82:1807–1821
Afzal M, Safer AM, Menon M (2015) Green tea polyphenols and their potential role in health and disease. Inflammopharmacology 23:151–161
Yao C, Zhang J, Liu G, Chen F, Lin Y (2014) Neuroprotection by (−)-epigallocatechin-3-gallate in a rat model of stroke is mediated through inhibition of endoplasmic reticulum stress. Mol Med Rep 9:69–76
Zhang F, Li N, Jiang L, Chen L, Huang M (2015) Neuroprotective effects of (−)-epigallocatechin-3-gallate against focal cerebral ischemia/reperfusion injury in rats through attenuation of inflammation. Neurochem Res 40:1691–1698
Xie W, Ramakrishna N, Wieraszko A, Hwang YW (2008) Promotion of neuronal plasticity by (−)-epigallocatechin-3-gallate. Neurochem Res 33:776–783
van Praag H, Lucero MJ, Yeo GW, Stecker K, Heivand N, Zhao C, Yip E, Afanador M et al (2007) Plant-derived flavanol (−)epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci 27:5869–5878
Wang Y, Li M, Xu X, Song M, Tao H, Bai Y (2012) Green tea epigallocatechin-3-gallate (EGCG) promotes neural progenitor cell proliferation and sonic hedgehog pathway activation during adult hippocampal neurogenesis. Mol Nutr Food Res 56:1292–1303
Itoh T, Imano M, Nishida S, Tsubaki M, Mizuguchi N, Hashimoto S, Ito A, Satou T (2012) (−)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury. J Neural Transm (Vienna) 119:877–890
Zhang J, Mao X, Zhou T, Cheng X, Lin Y (2014) IL-17A contributes to brain ischemia reperfusion injury through calpain-TRPC6 pathway in mice. Neuroscience 274:419–428
Zhang J, Wu Y, Weng Z, Zhou T, Feng T, Lin Y (2014) Glycyrrhizin protects brain against ischemia-reperfusion injury in mice through HMGB1-TLR4-IL-17A signaling pathway. Brain Res 1582:176–186
Sun F, Wang X, Mao X, Xie L, Jin K (2012) Ablation of neurogenesis attenuates recovery of motor function after focal cerebral ischemia in middle-aged mice. PLoS One 7:e46326
Gertz K, Kronenberg G, Kalin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmann-Regen J et al (2012) Essential role of interleukin-6 in post-stroke angiogenesis. Brain 135:1964–1980
Song J, Cho KJ, Cheon SY, Kim SH, Park KA, Lee WT, Lee JE (2013) Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp Mol Med 45:e69
Shin JA, Lim SM, Jeong SI, Kang JL, Park EM (2014) Noggin improves ischemic brain tissue repair and promotes alternative activation of microglia in mice. Brain Behav Immun 40:143–154
Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171
Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, Nygren JM, Jacobsen SE et al (2009) Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57:835–849
Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070
Brifault C, Gras M, Liot D, May V, Vaudry D, Wurtz O (2015) Delayed pituitary adenylate cyclase-activating polypeptide delivery after brain stroke improves functional recovery by inducing m2 microglia/macrophage polarization. Stroke 46:520–528
Xu D, Zhang F, Wang Y, Sun Y, Xu Z (2014) Microcephaly-associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex. Cell Rep 6:104–116
Zhang D, Guo M, Zhang W, Lu XY (2011) Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3beta (GSK-3beta)/beta-catenin signaling cascade. J Biol Chem 286:44913–44920
Zhang C, Chopp M, Cui Y, Wang L, Zhang R, Zhang L, Lu M, Szalad A et al (2010) Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res 88:3275–3281
Rosa AI, Goncalves J, Cortes L, Bernardino L, Malva JO, Agasse F (2010) The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells. J Neurosci 30:4573–4584
Nicoleau C, Benzakour O, Agasse F, Thiriet N, Petit J, Prestoz L, Roger M, Jaber M et al (2009) Endogenous hepatocyte growth factor is a niche signal for subventricular zone neural stem cell amplification and self-renewal. Stem Cells 27:408–419
Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970
Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813
Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, Ekdahl CT, Kokaia Z et al (2006) Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24:739–747
Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M et al (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53:743–751
Shioda N, Han F, Morioka M, Fukunaga K (2008) Bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) enhances neurogenesis via phosphatidylinositol 3-kinase/Akt and extracellular signal regulated kinase activation in the hippocampal subgranular zone after mouse focal cerebral ischemia. Neuroscience 155:876–887
Fan W, Dai Y, Xu H, Zhu X, Cai P, Wang L, Sun C, Hu C et al (2014) Caspase-3 modulates regenerative response after stroke. Stem Cells 32:473–486
Gregorian C, Nakashima J, Le Belle J, Ohab J, Kim R, Liu A, Smith KB, Groszer M et al (2009) Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. J Neurosci 29:1874–1886
SYY, YL, and JCZ contributed in the experimental design. JCZ, HX, and YY contributed in the stroke model, functional assays, and Western blotting. JCZ, YY, JYC, and YJZ helped in the immunocytochemistry and functional assays. JCZ helped in the neurosphere cultures. JCZ contributed in the imaging tools. SYY, YL, and JCZ contributed in the data analysis. JCZ wrote the article
Sources of Funding
This work was supported by the Huazhong University of Science and Technology Innovation fund (0118530238) and the National Natural Science Foundation of China (Grant Nos. 81571138, 81571286).
Jian-Cheng Zhang and Hang Xu are joint first authors.
Yun Lin and Shiying Yuan are joint last authors.
About this article
Cite this article
Zhang, J., Xu, H., Yuan, Y. et al. Delayed Treatment with Green Tea Polyphenol EGCG Promotes Neurogenesis After Ischemic Stroke in Adult Mice. Mol Neurobiol 54, 3652–3664 (2017). https://doi.org/10.1007/s12035-016-9924-0
- Ischemic stroke
- Neural progenitors