{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:04:21Z","timestamp":1789949061033,"version":"4.0.1"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T00:00:00Z","timestamp":1515110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg\/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2\u2032-deoxyuridine was injected at days 8\u201310 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect.<\/jats:p>","DOI":"10.3390\/ijms19010162","type":"journal-article","created":{"date-parts":[[2018,1,8]],"date-time":"2018-01-08T04:21:21Z","timestamp":1515385281000},"page":"162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-0674","authenticated-orcid":false,"given":"Marina","family":"Khodanovich","sequence":"first","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Kisel","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kudabaeva","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Chernysheva","sequence":"additional","affiliation":[{"name":"E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, 3, Lenina Ave., Tomsk 634028, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Smolyakova","sequence":"additional","affiliation":[{"name":"E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, 3, Lenina Ave., Tomsk 634028, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Krutenkova","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Wasserlauf","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-6586","authenticated-orcid":false,"given":"Mark","family":"Plotnikov","sequence":"additional","affiliation":[{"name":"E.D. Goldberg Institute of Pharmacology and Regenerative Medicine, 3, Lenina Ave., Tomsk 634028, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasily","family":"Yarnykh","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia"},{"name":"Department of Radiology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.1083328","article-title":"Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants","volume":"301","author":"Santarelli","year":"2003","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9104","DOI":"10.1523\/JNEUROSCI.20-24-09104.2000","article-title":"Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus","volume":"20","author":"Malberg","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8233","DOI":"10.1073\/pnas.0601992103","article-title":"Fluoxetine targets early progenitor cells in the adult brain","volume":"103","author":"Encinas","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1523\/JNEUROSCI.3632-07.2008","article-title":"Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells","volume":"28","author":"Wang","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pnpbp.2014.10.017","article-title":"Influence of enrichment on behavioral and neurogenic effects of antidepressants in Wistar rats submitted to repeated forced swim test","volume":"58","author":"Possamai","year":"2015","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Klomp, A., V\u00e1clav\u016f, L., Meerhoff, G.F., Reneman, L., and Lucassen, P.J. (2014). Effects of Chronic Fluoxetine Treatment on Neurogenesis and Tryptophan Hydroxylase Expression in Adolescent and Adult Rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097603"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/jnr.21829","article-title":"Chronic Fluoxetine Treatment Improves Ischemia-Induced Spatial Cognitive Deficits Through Increasing Hippocampal Neurogenesis After Stroke","volume":"87","author":"Li","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1161\/STROKEAHA.114.006304","article-title":"Efficacy of antidepressants in animal models of ischemic stroke: A systematic review and meta-analysis","volume":"45","author":"McCann","year":"2014","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neulet.2015.06.061","article-title":"Fluoxetine enhanced neurogenesis is not translated to functional outcome in stroke rats","volume":"603","author":"Sun","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s10517-016-3412-4","article-title":"Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats","volume":"161","author":"Khodanovich","year":"2016","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.pnpbp.2009.03.022","article-title":"Notch1 signaling, hippocampal neurogenesis and behavioral responses to chronic unpredicted mild stress in adult ischemic rats","volume":"33","author":"Guo","year":"2009","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.cell.2008.01.033","article-title":"Mechanisms and Functional Implications of Adult Neurogenesis","volume":"132","author":"Zhao","year":"2008","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pneurobio.2009.02.001","article-title":"Cell migration in the normal and pathological postnatal mammalian brain","volume":"88","author":"Cayre","year":"2009","journal-title":"Prog. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.neures.2008.01.008","article-title":"Ischemia induces cell proliferation and neurogenesis in the gerbil hippocampus in response to neuronal death","volume":"61","author":"Lanciego","year":"2008","journal-title":"Neurosci. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s002210000591","article-title":"Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat","volume":"136","author":"Kee","year":"2001","journal-title":"Exp. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7768","DOI":"10.1523\/JNEUROSCI.18-19-07768.1998","article-title":"Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils","volume":"18","author":"Liu","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0092-8674(02)00862-0","article-title":"Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors","volume":"110","author":"Nakatomi","year":"2002","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1161\/01.STR.32.8.1890","article-title":"Neurogenesis by progenitor cells in the ischemic adult rat hippocampus","volume":"32","author":"Yagita","year":"2001","journal-title":"Stroke"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.neuint.2007.04.011","article-title":"Repairing brain after stroke: A review on post-ischemic neurogenesis","volume":"50","author":"Wiltrout","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1161\/01.STR.0000173151.36031.be","article-title":"Stroke-induced neurogenesis in aged brain","volume":"36","author":"Darsalia","year":"2005","journal-title":"Stroke"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"i162","DOI":"10.1093\/cercor\/bhj174","article-title":"Regulation of Stroke-Induced Neurogenesis in Adult Brain\u2014Recent Scientific Progress","volume":"16","author":"Kokaia","year":"2006","journal-title":"Cereb. Cortex"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1634\/stemcells.2005-0281","article-title":"Persistent production of neurons from adult brain stem cells during recovery after stroke","volume":"24","author":"Thored","year":"2006","journal-title":"Stem Cells"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1161\/01.STR.32.5.1201","article-title":"Cortical Neurogenesis in Adult Rats After Transient Middle Cerebral Artery Occlusion","volume":"32","author":"Jiang","year":"2001","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0006-8993(01)02399-X","article-title":"Induction of highly polysialylated neural cell adhesion molecule (PSA-NCAM) in postischemic gerbil hippocampus mainly dissociated with neural stem cell proliferation","volume":"902","author":"Iwai","year":"2001","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1002\/jnr.21899","article-title":"Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect","volume":"87","author":"Lim","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.neuropharm.2013.11.011","article-title":"Fluoxetine inhibits transient global ischemia-induced hippocampal neuronal death and memory impairment by preventing blood-brain barrier disruption","volume":"79","author":"Lee","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.4196\/kjpp.2009.13.3.257","article-title":"Fluoxetine and sertraline attenuate postischemic brain injury in mice","volume":"13","author":"Shin","year":"2009","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.expneurol.2007.01.008","article-title":"Effects of fluoxetine in ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampal CA1 region induced by transient ischemia","volume":"204","author":"Kim","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.resuscitation.2011.11.004","article-title":"Fluoxetine has neuroprotective effects after cardiac arrest and cardiopulmonary resuscitation in mouse","volume":"83","author":"Taguchi","year":"2012","journal-title":"Resuscitation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s10517-014-2721-8","article-title":"Evaluation of survival and neurological deficit in rats in the new model of global transient cerebral ischemia","volume":"158","author":"Chernysheva","year":"2014","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.brainresbull.2017.06.005","article-title":"An improved three-vessel occlusion model of global cerebral ischemia in rats","volume":"132","author":"Atochin","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_32","first-page":"211","article-title":"Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats","volume":"17","author":"Jolkkonen","year":"2000","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.brainres.2005.02.060","article-title":"Fluoxetine and recovery of motor function after focal ischemia in rats","volume":"1044","author":"Windle","year":"2005","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/jnen\/62.2.127","article-title":"Inflammatory Mechanisms after Ischemia and Stroke","volume":"62","author":"Danton","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e00231","DOI":"10.1002\/prp2.231","article-title":"Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine","volume":"4","author":"Caiaffo","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.stem.2011.03.010","article-title":"Division-Coupled Astrocytic Differentiation and Age-Related Depletion of Neural Stem Cells in the Adult Hippocampus","volume":"8","author":"Encinas","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1001\/archneur.1977.00500180028006","article-title":"Experimental cerebral infarction effects on pentobarbital in Mongolian gerbils","volume":"34","author":"McGraw","year":"1977","journal-title":"Arch. Neurol."},{"key":"ref_38","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates, Academic Press. [6th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:50:15Z","timestamp":1760194215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,5]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["ijms19010162"],"URL":"https:\/\/doi.org\/10.3390\/ijms19010162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,5]]}}}