{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:01:15Z","timestamp":1787662875321,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,5,24]],"date-time":"2015-05-24T00:00:00Z","timestamp":1432425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recent findings indicate that fingolimod, the first oral drug approved for the treatment of multiple sclerosis (<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>), acts as a direct inhibitor of histone deacetylases (<jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content>s) and enhances the production of brain\u2010derived neurotrophic factor (<jats:styled-content style=\"fixed-case\">BDNF<\/jats:styled-content>) in the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>. Both mechanisms are relevant to the pathophysiology and treatment of major depression. We examined the antidepressant activity of fingolimod in mice subjected to chronic unpredictable stress (<jats:styled-content style=\"fixed-case\">CUS<\/jats:styled-content>), a model of reactive depression endowed with face and pharmacological validity. Chronic treatment with fingolimod (3\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>, i.p., once a day for 4\u00a0weeks) reduced the immobility time in the forced swim test (<jats:styled-content style=\"fixed-case\">FST<\/jats:styled-content>) in a large proportion of <jats:styled-content style=\"fixed-case\">CUS<\/jats:styled-content> mice. This treatment also caused anxiogenic\u2010like effects in the social interaction test without affecting anxiety\u2010like behavior in the elevated plus maze or spatial learning in the water maze. <jats:styled-content style=\"fixed-case\">CUS<\/jats:styled-content> mice showed reduced <jats:styled-content style=\"fixed-case\">BDNF<\/jats:styled-content> levels and enhanced <jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content>2 levels in the hippocampus. These changes were reversed by fingolimod exclusively in mice that showed a behavioral response to the drug in the <jats:styled-content style=\"fixed-case\">FST<\/jats:styled-content>. Fingolimod treatment also enhanced H3 histone K14\u2010acetylation and adult neurogenesis in the hippocampus of <jats:styled-content style=\"fixed-case\">CUS<\/jats:styled-content> mice. Fingolimod did not affect most of the parameters we have tested in unstressed control mice. The antidepressant\u2010like activity of fingolimod was confirmed in mice chronically treated with corticosterone. These findings show for the first time that fingolimod exerts antidepressant\u2010like effect acting in a \u201cdisease\u2010dependent\u201d manner, and raise the interesting possibility that the drug could relieve depressive symptoms in <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> patients independently of its disease\u2010modifying effect on <jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/prp2.135","type":"journal-article","created":{"date-parts":[[2015,6,12]],"date-time":"2015-06-12T12:05:03Z","timestamp":1434110703000},"source":"Crossref","is-referenced-by-count":49,"title":["Antidepressant activity of fingolimod in mice"],"prefix":"10.1002","volume":"3","author":[{"given":"Luigi","family":"di Nuzzo","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosamaria","family":"Orlando","sequence":"additional","affiliation":[{"name":"IRCCS Associazione Oasi Maria S.S. Institute for Research on Mental Retardation and Brain Aging Troina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Tognoli","sequence":"additional","affiliation":[{"name":"Department of Neurological and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Di Pietro","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Bertini","sequence":"additional","affiliation":[{"name":"Department of Neurological and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Bucci","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Motolese","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Scaccianoce","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Mauro","sequence":"additional","affiliation":[{"name":"Institute of Psychiatry Catholic University of Sacred Heart Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"De Lucia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Battaglia","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"},{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Francesco","family":"Fabene","sequence":"additional","affiliation":[{"name":"Department of Neurological and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology University Sapienza of Rome Rome Italy"},{"name":"IRCCS Neuromed Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,5,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.09.008"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2010.76"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00564-5"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-011-1196-4"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3248"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014154108"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458513502572"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61620-7"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.02.022"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2013.121"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/09638280500191753"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.04.017"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206093109"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061988"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.09.010"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-007-2017-2"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458511417835"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.04.060"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1978.tb07001.x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.03.046"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142301.ns0932s49"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10849"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.1987.tb02837.x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3728"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.02.017"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.220"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.01.007"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.01.008"},{"key":"e_1_2_8_30_1","unstructured":"HunterJW HollanderE MillerDM CutterG AgashivalaN LiS et\u00a0al. (2013)Impact of Fingolimod on depressive symptoms: post hoc data from the EPOC trial. 29th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis. 2\u20135 October Copenhagen Denmark P2010."},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.08.078"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbrainres.2004.12.020"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1046-2023(02)00235-9"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910658107"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2009.10030434"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2010_108"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1586\/ern.12.98"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.11.029"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000013"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2007.07101634"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2647"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.15-11-07539.1995"},{"key":"e_1_2_8_43_1","first-page":"555","article-title":"Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis","volume":"8","author":"Nuzzo L","year":"2014","journal-title":"Drug Des Devel Ther"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1191\/1352458505ms1144oa"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMct1101691"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142301.ns0810as14"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2004.04.008"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(96)00058-9"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083328"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.05.005"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(03)00181-1"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-08-03251.2002"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.73"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2009.67"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fprp2.135","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fprp2.135","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.135","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:59:30Z","timestamp":1696208370000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,24]]},"references-count":53,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2015,6]]}},"alternative-id":["10.1002\/prp2.135"],"URL":"https:\/\/doi.org\/10.1002\/prp2.135","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,5,24]]},"article-number":"e00135"}}