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Consequently, the current study tested the hypothesis that SIM confers neuroprotection in\u00a0a rodent model of depressive\u2010like phenotypes induced by Doxorubicin (DOX)\/Cyclophosphamide (CP) polychemotherapy. Rats were divided into four cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910 per group). Control; SIM\u2010alone; chemotherapy; SIM\/chemotherapy combination. SIM co\u2010treatment significantly improved depression\u2010like phenotypes throughout the forced swim test, the sucrose splash test as well as the open field test. This is in addition to alleviating hippocampal neuro\u2010inflammation and oxidative stress vs the chemotherapy\u2010combination group. Concurrently, SIM reduced hippocampal oxidative stress (51% decrease in MDA) and inflammation (70% and 42% decrease in TNF\u2010\u03b1 and NF\u2010\u03baB). SIM also attenuated apoptosis (29% reduction in active caspase\u20103). Pathway enrichment (PEA) and Gene Ontology (GO) analyses supported that SIM's cytoprotective effects may be mediated through multiple pathways, including lipid metabolism, immunity, and apoptosis regulation. In conclusion, SIM co\u2010administration effectively attenuated the molecular alterations elicited by the DOX\/CP combination within the hippocampal tissues. Collectively, these data position SIM as a promising candidate for mitigating chemotherapy\u2010associated depression. Nevertheless, further investigation is warranted to fully elucidate the underlying antidepressant mechanisms of statins and to validate their clinical efficacy.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70332","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:29:02Z","timestamp":1791181742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Simvastatin Mitigates Chemotherapy\u2010Induced Depressive\u2010Like Behaviors in Rats"],"prefix":"10.1002","volume":"359","author":[{"given":"Heba A.","family":"Elbadawy","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-7173","authenticated-orcid":false,"given":"Marwa A.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9531-2266","authenticated-orcid":false,"given":"Eman","family":"Badr","sequence":"additional","affiliation":[{"name":"Center for Genomics, Helmy Institute for Medical Sciences University of Science and Technology Zewail City Giza Egypt"},{"name":"Faculty of Computers and Artificial Intelligence Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaimaa G.","family":"Gahin","sequence":"additional","affiliation":[{"name":"Center for Genomics, Helmy Institute for Medical Sciences University of Science and Technology Zewail City Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem N.","family":"El\u2010Naga","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2559-6299","authenticated-orcid":false,"given":"Mai F.","family":"Tolba","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University Cairo Egypt"},{"name":"Translational Research Department Shefa Al Orman Hospital Luxor Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2073"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_202109_26799"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2000"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-31939-9"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e32833ffb56"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9125601"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-021-01092-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1191\/0960327103ht388oa"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.4103\/1735-5362.236837"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfz213"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.06.005"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1r127"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2021.702617"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2018.09.022"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-019-05406-w"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.07.003"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107582"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.17712\/1658-3183.1914","article-title":"Acute Antidepressant and Anxiolytic Effects of Simvastatin and Its Mechanisms in Rats","volume":"17","author":"Kilic F. 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