{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:54:27Z","timestamp":1772643267884,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,2,8]],"date-time":"2017-02-08T00:00:00Z","timestamp":1486512000000},"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>The aim of this study was to determine the effects and underlying mechanism of aripiprazole (APZ) augmentation for cilostazol (CLS)-treated post-ischemic stroke mice that were exposed to chronic mild stress (CMS). Compared to treatment with either APZ or CLS alone, the combined treatment resulted in a greater reduction in depressive behaviors, including anhedonia, despair-like behaviors, and memory impairments. This treatment also significantly reduced atrophic changes in the striatum, cortex, and midbrain of CMS-treated ischemic mice, and inhibited neuronal cell apoptosis, particularly in the striatum and the dentate gyrus of the hippocampus. Greater proliferation of neuronal progenitor cells was also observed in the ipsilateral striatum of the mice receiving combined treatment compared to mice receiving either drug alone. Phosphorylation of the cyclic adenosine monophosphate response element binding protein (CREB) was increased in the striatum, hippocampus, and midbrain of mice receiving combined treatment compared to treatment with either drug alone, particularly in the neurons of the striatum and hippocampus, and dopaminergic neurons of the midbrain. Our results suggest that APZ may augment the antidepressant effects of CLS via co-regulation of the CREB signaling pathway, resulting in the synergistic enhancement of their neuroprotective effects.<\/jats:p>","DOI":"10.3390\/ijms18020355","type":"journal-article","created":{"date-parts":[[2017,2,10]],"date-time":"2017-02-10T05:27:09Z","timestamp":1486704429000},"page":"355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Antidepressant Effects of Aripiprazole Augmentation for Cilostazol-Treated Mice Exposed to Chronic Mild Stress after Ischemic Stroke"],"prefix":"10.3390","volume":"18","author":[{"given":"Yu","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"},{"name":"Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ha","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"},{"name":"Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ki","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hwa","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"},{"name":"Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan 50612, Korea"},{"name":"Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5965-4346","authenticated-orcid":false,"given":"Byung","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"},{"name":"Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan 50612, Korea"},{"name":"Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1111\/bph.12775","article-title":"Of mice and men: Modelling post-stroke depression experimentally","volume":"171","author":"Kronenberg","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1001\/archpsyc.1997.01830220033006","article-title":"\u201cVascular depression\u201d hypothesis","volume":"54","author":"Alexopoulos","year":"1997","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_3","first-page":"161","article-title":"Cerebrovascular diseases and depression: Epidemiology, mechanisms and treatment","volume":"54","author":"Gothe","year":"2012","journal-title":"Panminerva Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1017\/S0317167100012610","article-title":"Inflammatory demyelinating brain lesions heralding primary CNS lymphoma","volume":"39","author":"Husseini","year":"2012","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10522-014-9516-1","article-title":"Perfusion deficits, inflammation and aging precipitate depressive behaviour","volume":"15","author":"Buga","year":"2014","journal-title":"Biogerontology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1097\/FBP.0b013e3283618afe","article-title":"Cerebral ischemia-induced difference in sensitivity to depression and potential therapeutics in rats","volume":"24","author":"Sun","year":"2013","journal-title":"Behav. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1111\/j.1582-4934.2012.01555.x","article-title":"Post-stroke depression: Mechanisms, translation and therapy","volume":"16","author":"Loubinoux","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.bbr.2010.01.022","article-title":"The 5-HT7 receptor as a mediator and modulator of antidepressant-like behavior","volume":"209","author":"Sarkisyan","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.pnpbp.2010.11.010","article-title":"The WAG\/Rij strain: A genetic animal model of absence epilepsy with comorbidity of depression [corrected]","volume":"35","author":"Sarkisova","year":"2011","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1097\/00019442-200211000-00007","article-title":"Frontostriatal and limbic dysfunction in late-life depression","volume":"10","author":"Alexopoulos","year":"2002","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1136\/jnnp.2007.124651","article-title":"White matter hyperintensities in late life depression: A systematic review","volume":"79","author":"Herrmann","year":"2008","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/S1734-1140(11)70605-3","article-title":"Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats","volume":"63","author":"Burda","year":"2011","journal-title":"Pharmacol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.neuropharm.2012.06.039","article-title":"Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity","volume":"64","author":"Russo","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"965","DOI":"10.2147\/NDT.S63290","article-title":"Two cases of emotional disorder after middle cerebral artery infarction showing distinct responses to antidepressant treatment","volume":"10","author":"Shimoda","year":"2014","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.2174\/1381612033453910","article-title":"Cilostazol as a unique antithrombotic agent","volume":"9","author":"Kambayashi","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.neuroscience.2010.10.008","article-title":"Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia","volume":"171","author":"Tanaka","year":"2010","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.nbd.2014.08.034","article-title":"Diabetes augments cognitive dysfunction in chronic cerebral hypoperfusion by increasing neuronal cell death: Implication of cilostazol for diabetes mellitus-induced dementia","volume":"73","author":"Kwon","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1161\/STROKEAHA.110.609834","article-title":"Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats","volume":"42","author":"Oyama","year":"2011","journal-title":"Stroke"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00401-012-0990-8","article-title":"NF-\u03baB contributes to the detrimental effects of social isolation after experimental stroke","volume":"124","author":"Venna","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.psyneuen.2011.09.007","article-title":"Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL\/6J mice","volume":"37","author":"Berry","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.bbr.2015.03.062","article-title":"Studies on the animal model of post-stroke depression and application of antipsychotic aripiprazole","volume":"287","author":"Kim","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.biopsych.2012.02.026","article-title":"Exofocal dopaminergic degeneration as antidepressant target in mouse model of poststroke depression","volume":"72","author":"Kronenberg","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1124\/jpet.300.3.787","article-title":"Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats","volume":"300","author":"Choi","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/S1474-4422(10)70198-8","article-title":"Cilostazol for prevention of secondary stroke (CSPS 2): An aspirin-controlled, double-blind, randomised non-inferiority trial","volume":"9","author":"Shinohara","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21663","DOI":"10.1074\/jbc.M115.664920","article-title":"Nuclear translocation of calcium\/calmodulin-dependent protein kinase II\u03b43 promoted by protein phosphatase-1 enhances brain-derived neurotrophic factor expression in dopaminergic neurons","volume":"290","author":"Shioda","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_26","first-page":"250","article-title":"Focus on aripiprazole: A review of its use in child and adolescent psychiatry","volume":"18","author":"Greenaway","year":"2009","journal-title":"J. Can. Acad. Child Adolesc. Psychiatry"},{"key":"ref_27","first-page":"103.e7","article-title":"Aripiprazole improves various cognitive and behavioral impairments after traumatic brain injury: A case report","volume":"35","author":"Yoshimura","year":"2013","journal-title":"Gen. Hosp. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.pneurobio.2009.10.019","article-title":"Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation","volume":"90","author":"Manda","year":"2010","journal-title":"Prog. Neurobiol."},{"key":"ref_29","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."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2049-9256-1-14","article-title":"Post-stroke depression and the aging brain","volume":"1","author":"Cojocaru","year":"2013","journal-title":"J. Mol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ejphar.2010.10.064","article-title":"Aripiprazole protects cortical neurons from glutamate toxicity","volume":"651","author":"Koprivica","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1007\/s11064-013-1104-2","article-title":"Aripiprazole, an atypical antipsychotic drug, improves maturation and complexity of neuroblast dendrites in the mouse dentate gyrus via increasing superoxide dismutases","volume":"38","author":"Chen","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1124\/jpet.103.061853","article-title":"Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats","volume":"308","author":"Lee","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1176\/jnp.2007.19.4.471","article-title":"Cilostazol, a cAMP phosphodiesterase 3 inhibitor, in the treatment of poststroke depression","volume":"19","author":"Nishimura","year":"2007","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/stem.56","article-title":"cAMP response element binding protein is required for mouse neural progenitor cell survival and expansion","volume":"27","author":"Dworkin","year":"2009","journal-title":"Stem Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.brainres.2006.01.088","article-title":"Neuroprotection by cilostazol, a phosphodiesterase type 3 inhibitor, against apoptotic white matter changes in rat after chronic cerebral hypoperfusion","volume":"1082","author":"Lee","year":"2006","journal-title":"Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.neuroscience.2009.05.004","article-title":"Crucial role for ser133-phosphorylated form of cyclic AMP-responsive element binding protein signaling in the differentiation and survival of neural progenitors under chronic cerebral hypoperfusion","volume":"162","author":"Miyamoto","year":"2009","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.neures.2011.01.004","article-title":"Protective effects of atypical antipsychotic drugs against MPP+-induced oxidative stress in PC12 cells","volume":"69","author":"Park","year":"2011","journal-title":"Neurosci. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1007\/s11064-007-9289-x","article-title":"Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain","volume":"32","author":"Eren","year":"2007","journal-title":"Neurochem Res."},{"key":"ref_40","first-page":"6107","article-title":"Calcium\/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression","volume":"14","author":"Matthews","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17957","DOI":"10.1074\/jbc.271.30.17957","article-title":"Calmodulin-dependent protein kinase II potentiates transcriptional activation through activating transcription factor 1 but not camp response element-binding protein","volume":"271","author":"Shimomura","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1161\/STROKEAHA.113.001530","article-title":"Age-related decline in oligodendrogenesis retards white matter repair in mice","volume":"44","author":"Miyamoto","year":"2013","journal-title":"Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s00213-015-4185-6","article-title":"Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke","volume":"233","author":"Kim","year":"2015","journal-title":"Psychopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1254\/jphs.08201SC","article-title":"Potentiation of the antidepressant-like effect of fluoxetine by aripiprazole in the mouse tail suspension test","volume":"108","author":"Kamei","year":"2008","journal-title":"J. Pharmacol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/BF00187257","article-title":"Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant","volume":"93","author":"Willner","year":"1987","journal-title":"Psychopharmacology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1073\/pnas.0910658107","article-title":"Nuclear factor-\u03baB is a critical mediator of stress-impaired neurogenesis and depressive behavior","volume":"107","author":"Koo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8493","DOI":"10.1523\/JNEUROSCI.1321-09.2009","article-title":"Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors","volume":"29","author":"Lee","year":"2009","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/355\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:42Z","timestamp":1760207262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,8]]},"references-count":47,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["ijms18020355"],"URL":"https:\/\/doi.org\/10.3390\/ijms18020355","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,8]]}}}