{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:07:49Z","timestamp":1783134469061,"version":"3.54.6"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,5,9]],"date-time":"2020-05-09T00:00:00Z","timestamp":1588982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Medicinal Materials, Hanoi, Vietnam","award":["17-2016\/HD-DTCS"],"award-info":[{"award-number":["17-2016\/HD-DTCS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and promotes TMT-induced hippocampal neurogenesis. In this study, we demonstrate that administration of BME improves spatial working memory in adolescent (5-week- old) healthy mice but not adult (8-week-old) mice. Moreover, improved spatial working memory was retained even at 4 weeks after terminating 1-week treatment of adolescent mice. One-week BME treatment of adolescent mice significantly enhanced hippocampal BrdU incorporation and expression of genes involved in neurogenesis determined by RNAseq analysis. Cell death, as detected by histochemistry, appeared not to be significant. A significant increase in neurogenesis was observed in the dentate gyrus region 4 weeks after terminating 1-week treatment of adolescent mice with BME. Bacopaside I, an active component of BME, promoted the proliferation of neural progenitor cells in vitro in a concentration-dependent manner via the facilitation of the Akt and ERK1\/2 signaling. These results suggest that BME enhances spatial working memory in healthy adolescent mice by promoting hippocampal neurogenesis and that the effects of BME are due, in significant amounts, to bacopaside I.<\/jats:p>","DOI":"10.3390\/ijms21093365","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T10:01:18Z","timestamp":1589191278000},"page":"3365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Bacopa monnieri (L.) Wettst. Extract Improves Memory Performance via Promotion of Neurogenesis in the Hippocampal Dentate Gyrus of Adolescent Mice"],"prefix":"10.3390","volume":"21","author":[{"given":"Hang Thi Nguyet","family":"Pham","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Biochemistry, National Institute of Medicinal Materials, Hoan Kiem District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Nguyen","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry, National Institute of Medicinal Materials, Hoan Kiem District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong Thi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry, National Institute of Medicinal Materials, Hoan Kiem District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xoan Thi","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry, National Institute of Medicinal Materials, Hoan Kiem District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khoi Minh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry, National Institute of Medicinal Materials, Hoan Kiem District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinh Viet","family":"Phan","sequence":"additional","affiliation":[{"name":"National Geriatric Hospital, Dong Da District, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Yoneyama","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Setsunan University, Osaka 573-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyokazu","family":"Ogita","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Setsunan University, Osaka 573-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Setsunan University, Osaka 573-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Folk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamitsu","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 603-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinzo","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Kampo Pharmacology, Daiichi University of Pharmacy, Fukuoka 815-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1242\/dev.014977","article-title":"Neural stem cells: Balancing self-renewal with differentiation","volume":"135","author":"Doe","year":"2008","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.55782\/ane-2012-1904","article-title":"Endogenous neurogenesis induced by ischemic brain injury or neurodegenerative diseases in adults","volume":"72","author":"Zalewska","year":"2012","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev.pharmtox.44.101802.121631","article-title":"Neurogenesis in the adult brain: New strategies for central nervous system diseases","volume":"44","author":"Lie","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/stem.5530130307","article-title":"Neuronal stem cells in the brain of adult vertebrates","volume":"13","author":"Lois","year":"1995","journal-title":"Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1101\/lm.026542.112","article-title":"Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?","volume":"20","author":"Drew","year":"2013","journal-title":"Learn. Mem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yau, S.-Y., Li, A., and So, K.-F. (2015). Involvement of adult hippocampal neurogenesis in learning and forgetting. Neural Plast., 2015.","DOI":"10.1155\/2015\/717958"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/hipo.20153","article-title":"Is there a link between adult neurogenesis and learning?","volume":"16","author":"Leuner","year":"2006","journal-title":"Hippocampus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jep.2015.01.041","article-title":"Protective effects of Bacopa monnieri on ischemia-induced cognitive deficits in mice: The possible contribution of bacopaside I and underlying mechanism","volume":"164","author":"Le","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ctim.2019.03.016","article-title":"Neuropharmacological and cognitive effects of Bacopa monnieri (L.) Wettst\u2014A review on its mechanistic aspects","volume":"44","author":"Sukumaran","year":"2019","journal-title":"Complement. Ther. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1007\/s11064-013-1129-6","article-title":"Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: Possible involvement of glutamatergic and cholinergic systems","volume":"38","author":"Le","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1007\/s11064-007-9513-8","article-title":"Neuroprotective role of Bacopa monnieri extract in epilepsy and effect of glucose supplementation during hypoxia: Glutamate receptor gene expression","volume":"33","author":"Paulose","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s11064-010-0253-9","article-title":"Behavioral deficit and decreased GABA receptor functional regulation in the hippocampus of epileptic rats: Effect of Bacopa monnieri","volume":"36","author":"Mathew","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jns.2009.04.032","article-title":"Down-regulation of cerebellar 5-HT(2C) receptors in pilocarpine-induced epilepsy in rats: Therapeutic role of Bacopa monnieri extract","volume":"284","author":"Krishnakumar","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3233\/JAD-2006-9303","article-title":"Bacopa monniera extract reduces amyloid levels in PSAPP mice","volume":"9","author":"Holcomb","year":"2006","journal-title":"J. Alzheimers Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1248\/bpb.b19-00288","article-title":"Bacopa monnieri (L.) Wettst. Ameliorates cognitive deficits caused in a trimethyltin-induced neurotoxicity model mice","volume":"42","author":"Pham","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1111\/j.1460-9568.2007.05763.x","article-title":"Unbiased cell quantification reveals a continued increase in the number of neocortical neurones during early post-natal development in mice","volume":"26","author":"Lyck","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s00429-012-0462-x","article-title":"Cellular composition characterizing postnatal development and maturation of the mouse brain and spinal cord","volume":"218","author":"Fu","year":"2013","journal-title":"Brain Struct. Funct."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.jep.2011.04.010","article-title":"Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice","volume":"135","author":"Yamada","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3389\/fphar.2017.00678","article-title":"A randomized, double-blind study assessing changes in cognitive function in Indian school children receiving a combination of Bacopa monnieri and micronutrient supplementation vs. placebo","volume":"8","author":"Kalita","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_20","first-page":"663","article-title":"Learning and memory-enhancing effect of Bacopa monniera in neonatal rats","volume":"112","author":"Vollala","year":"2011","journal-title":"Bratisl. Lek. Listy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1126\/science.7777856","article-title":"Linked regularities in the development and evolution of mammalian brains","volume":"268","author":"Finlay","year":"1995","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1177\/0023677216653984","article-title":"Does age matter? The impact of rodent age on study outcomes","volume":"51","author":"Jackson","year":"2017","journal-title":"Lab. Anim."},{"key":"ref_23","first-page":"624","article-title":"The laboratory rat: Relating its age with human\u2019s","volume":"4","author":"Sengupta","year":"2013","journal-title":"Int. J. Prev. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0149-7634(00)00014-2","article-title":"The adolescent brain and age-related behavioral manifestations","volume":"24","author":"Spear","year":"2000","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1124\/pr.115.012138","article-title":"Adolescent alcohol exposure persistently impacts adult neurobiology and behavior","volume":"68","author":"Crews","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1016\/j.fct.2007.04.010","article-title":"Safety evaluation of a standardized phytochemical composition extracted from Bacopa monnieri in Sprague\u2013Dawley rats","volume":"45","author":"Allan","year":"2007","journal-title":"Food Chem. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1074\/jbc.M609712200","article-title":"Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity","volume":"282","author":"Rocher","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/nature04108","article-title":"Wnt signalling regulates adult hippocampal neurogenesis","volume":"437","author":"Lie","year":"2005","journal-title":"Nature"},{"key":"ref_29","first-page":"52","article-title":"IGF-I: A key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the Brain","volume":"10","author":"Defterali","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.yebeh.2016.12.007","article-title":"VEGF regulates hippocampal neurogenesis and reverses cognitive deficits in immature rats after status epilepticus through the VEGF R2 signaling pathway","volume":"68","author":"Han","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1127310","DOI":"10.1080\/23262133.2015.1127310","article-title":"Cholinergic circuit control of postnatal neurogenesis","volume":"3","author":"Asrican","year":"2016","journal-title":"Neurogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1111\/j.1460-9568.2011.07606.x","article-title":"CREB in adult neurogenesis\u2014Master and partner in the development of adult-born neurons?","volume":"33","author":"Merz","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1152\/physrev.00004.2014","article-title":"Regulation and function of adult neurogenesis: From genes to cognition","volume":"94","author":"Aimone","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.pbb.2006.11.003","article-title":"Neurogenesis decreases during brain maturation from adolescence to adulthood","volume":"86","author":"He","year":"2007","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1523\/JNEUROSCI.0862-13.2014","article-title":"In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer\u2019s disease model","volume":"34","author":"Vargas","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1007\/s11064-017-2360-3","article-title":"Antidepressant-like effect of bacopaside i in mice exposed to chronic unpredictable mild stress by modulating the hypothalamic-pituitary-adrenal axis function and activating BDNF signaling pathway","volume":"42","author":"Zu","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.neuroscience.2012.09.073","article-title":"Brain-derived neurotrophic factor and glucocorticoids: Reciprocal influence on the central nervous system","volume":"239","author":"Numakawa","year":"2013","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1017\/S1461145709000376","article-title":"Early induction of CREB activation and CREB-regulating signalling by antidepressants","volume":"12","author":"Tardito","year":"2009","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.3892\/ijmm.2017.2962","article-title":"The extracellular signal-regulated kinase 1\/2 pathway in neurological diseases: A potential therapeutic target (Review)","volume":"39","author":"Sun","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"705","DOI":"10.4161\/cc.8.5.7734","article-title":"Total ERK1\/2 activity regulates cell proliferation","volume":"8","author":"Lefloch","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_41","first-page":"850","article-title":"Akt3 is responsible for the survival and proliferation of embryonic stem cells","volume":"6","author":"Wang","year":"2017","journal-title":"Biol. Open"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0074-7742(09)85026-5","article-title":"Chapter 26 Role of Akt and Erk Signaling in the Neurogenesis Following Brain Ischemia","volume":"Volume 85","author":"Shioda","year":"2009","journal-title":"International Review of Neurobiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1523\/JNEUROSCI.21-05-01569.2001","article-title":"Activation of phosphatidylinositol-3 kinase (PI-3K) and extracellular regulated kinases (Erk1\/2) is involved in muscarinic receptor-mediated DNA synthesis in neural progenitor cells","volume":"21","author":"Li","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Yoneyama, M., Shiba, T., Hasebe, S., Umeda, K., Yamaguchi, T., and Ogita, K. (2014). Lithium promotes neuronal repair and ameliorates depression-like behavior following trimethyltin-induced neuronal loss in the dentate gyrus. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087953"},{"key":"ref_45","unstructured":"Paxinos, G., Keith, B.J., and Franklin, M. (2019). Paxinos and Franklin\u2019s the Mouse Brain in Stereotaxic Coordinates, Elsevier Science."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1177\/019262330002800111","article-title":"Fluoro-Jade: Novel fluorochromes for detecting toxicant-induced neuronal degeneration","volume":"28","author":"Schmued","year":"2000","journal-title":"Toxicol. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1038\/nprot.2016.095","article-title":"Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown","volume":"11","author":"Pertea","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/jnr.23472","article-title":"Beneficial effect of cilostazol-mediated neuronal repair following trimethyltin-induced neuronal loss in the dentate gyrus","volume":"93","author":"Yoneyama","year":"2015","journal-title":"J. Neurosci. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1254\/jphs.13201FP","article-title":"Beneficial in vivo effect of aripiprazole on neuronal regeneration following neuronal loss in the dentate gyrus: Evaluation using a mouse model of trimethyltin-induced neuronal loss\/self-repair in the dentate gyrus","volume":"124","author":"Yoneyama","year":"2014","journal-title":"J. Pharmacol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3365\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:27:19Z","timestamp":1760174839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,9]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21093365"],"URL":"https:\/\/doi.org\/10.3390\/ijms21093365","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,9]]}}}