Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery
5-Fluorouracil (5-FU) is a cytostatic drug associated with chemotherapy-induced cognitive impairments that many cancer patients experience after treatment. Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment,...
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| description | 5-Fluorouracil (5-FU) is a cytostatic drug associated with chemotherapy-induced cognitive impairments that many cancer patients experience after treatment. Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive and cellular effects of 5-FU. This provides information on the mechanism by which fluoxetine acts to protect against 5-FU and indicates when it would be beneficial to administer the antidepressant to cancer patients. |
| doi_str_mv | 10.1371/journal.pone.0030010 |
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Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive and cellular effects of 5-FU. This provides information on the mechanism by which fluoxetine acts to protect against 5-FU and indicates when it would be beneficial to administer the antidepressant to cancer patients.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0030010</identifier><identifier>PMID: 22272269</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; Animal behavior ; Animal cognition ; Animals ; Antidepressants ; Antidepressive Agents, Second-Generation - pharmacology ; Antimetabolites, Antineoplastic - adverse effects ; Apoptosis ; Biology ; Body Weight - drug effects ; Brain ; Brain research ; Bromodeoxyuridine - metabolism ; Cancer ; Cell cycle ; Cell growth ; Cell proliferation ; Cell Proliferation - drug effects ; Cell survival ; Chemo brain ; Chemotherapy ; Cognition Disorders - chemically induced ; Cognition Disorders - prevention & control ; Cognitive ability ; Dentate gyrus ; Dentate Gyrus - drug effects ; Dentate Gyrus - metabolism ; Dentate Gyrus - pathology ; Drinking - drug effects ; Drinking water ; Emotional disorders ; Experiments ; Fluorouracil ; Fluorouracil - adverse effects ; Fluoxetine ; Fluoxetine - pharmacology ; Hippocampus ; Hippocampus - drug effects ; Hippocampus - metabolism ; Hippocampus - pathology ; Immunohistochemistry ; Impairment ; Ki-67 Antigen - metabolism ; Kinases ; Laboratory animals ; Lymphoma ; Male ; Medicine ; Memory ; Memory - drug effects ; Memory tasks ; Neurogenesis ; Pancreatic cancer ; Patients ; Prevention ; Proteins ; Rats ; Recovery ; Recovery (Medical) ; Rodentia ; Rodents ; Serotonin ; Social and Behavioral Sciences ; Space Perception - drug effects ; Spatial analysis ; Spatial memory ; Stem cells ; Studies ; Survival ; Time Factors ; Weight Gain - drug effects</subject><ispartof>PloS one, 2012-01, Vol.7 (1), p.e30010</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Lyons et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive and cellular effects of 5-FU. 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drug effects</subject><subject>Memory tasks</subject><subject>Neurogenesis</subject><subject>Pancreatic cancer</subject><subject>Patients</subject><subject>Prevention</subject><subject>Proteins</subject><subject>Rats</subject><subject>Recovery</subject><subject>Recovery (Medical)</subject><subject>Rodentia</subject><subject>Rodents</subject><subject>Serotonin</subject><subject>Social and Behavioral Sciences</subject><subject>Space Perception - drug effects</subject><subject>Spatial analysis</subject><subject>Spatial memory</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Survival</subject><subject>Time Factors</subject><subject>Weight Gain - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk91q3DAQhU1padK0b1BaQ6HQi93Kli3bN4EQmnYhEOjfrRhL47WCLbmSvGTfow9cOeuENbRQdKG_7xwNB00UvU7IOqFF8vHWjFZDtx6MxjUhlJCEPIlOk4qmK5YS-vRofRK9cO6WkJyWjD2PTtI0LdKUVafR76tuNHfolcZYmFF7tCC8i3077bdaebXDGLSMBXbd2IGNsWlwQkwT56smyG2oBITqYqXvdRZ83KphMAL6YXRxvY8h7lG0oJXrJ91gcYfaK6MnuEUbdBDWKMwO7f5l9KyBzuGreT6Lflx9-n75ZXV983lzeXG9EqxK_IpR2TAsMqhkVWDZpJlMAVGwoshzSWgtWMqYyJggTQpZJpFIWVGoy6ypkprSs-jtwXfojONzoI4nNKWkKEo2EZsDIQ3c8sGqHuyeG1D8_sDYLQfrleiQAw3vJ7SEWsiMVKKUZSkRSaiLkbyavM7n18a6RylCABa6henyRquWb82O02CQVHkweDcbWPNrROf_UfJMbSFUpXRjgpnolRP8IisKErIhVaDWf6HCkNgrEb5Uo8L5QvBhIQiMxzu_hdE5vvn29f_Zm59L9v0R2yJ0vnWmG6fP4ZZgdgCFNc5ZbB6TSwifOuIhDT51BJ87IsjeHKf-KHpoAfoH-UgJzw</recordid><startdate>20120117</startdate><enddate>20120117</enddate><creator>Lyons, Laura</creator><creator>ElBeltagy, Maha</creator><creator>Bennett, Geoffrey</creator><creator>Wigmore, Peter</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120117</creationdate><title>Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery</title><author>Lyons, Laura ; ElBeltagy, Maha ; Bennett, Geoffrey ; Wigmore, Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-63df6e74a9d97e8f24d2aeec67755d03bc6266c46c0f2a44de0dd93ab84f91b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>5-Fluorouracil</topic><topic>Animal behavior</topic><topic>Animal cognition</topic><topic>Animals</topic><topic>Antidepressants</topic><topic>Antidepressive Agents, Second-Generation - 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Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive and cellular effects of 5-FU. This provides information on the mechanism by which fluoxetine acts to protect against 5-FU and indicates when it would be beneficial to administer the antidepressant to cancer patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22272269</pmid><doi>10.1371/journal.pone.0030010</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1323077863 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 5-Fluorouracil Animal behavior Animal cognition Animals Antidepressants Antidepressive Agents, Second-Generation - pharmacology Antimetabolites, Antineoplastic - adverse effects Apoptosis Biology Body Weight - drug effects Brain Brain research Bromodeoxyuridine - metabolism Cancer Cell cycle Cell growth Cell proliferation Cell Proliferation - drug effects Cell survival Chemo brain Chemotherapy Cognition Disorders - chemically induced Cognition Disorders - prevention & control Cognitive ability Dentate gyrus Dentate Gyrus - drug effects Dentate Gyrus - metabolism Dentate Gyrus - pathology Drinking - drug effects Drinking water Emotional disorders Experiments Fluorouracil Fluorouracil - adverse effects Fluoxetine Fluoxetine - pharmacology Hippocampus Hippocampus - drug effects Hippocampus - metabolism Hippocampus - pathology Immunohistochemistry Impairment Ki-67 Antigen - metabolism Kinases Laboratory animals Lymphoma Male Medicine Memory Memory - drug effects Memory tasks Neurogenesis Pancreatic cancer Patients Prevention Proteins Rats Recovery Recovery (Medical) Rodentia Rodents Serotonin Social and Behavioral Sciences Space Perception - drug effects Spatial analysis Spatial memory Stem cells Studies Survival Time Factors Weight Gain - drug effects |
| title | Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T10%3A23%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fluoxetine%20counteracts%20the%20cognitive%20and%20cellular%20effects%20of%205-fluorouracil%20in%20the%20rat%20hippocampus%20by%20a%20mechanism%20of%20prevention%20rather%20than%20recovery&rft.jtitle=PloS%20one&rft.au=Lyons,%20Laura&rft.date=2012-01-17&rft.volume=7&rft.issue=1&rft.spage=e30010&rft.pages=e30010-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0030010&rft_dat=%3Cgale_plos_%3EA477075509%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1323077863&rft_id=info:pmid/22272269&rft_galeid=A477075509&rft_doaj_id=oai_doaj_org_article_a324d138abcd409c8d88dee08f260593&rfr_iscdi=true |