Abstract
ABSTRACT
Beyond its primary lipid‐lowering efficacy, simvastatin (SIM) demonstrates neuroprotective potential mediated by its antioxidant, anti‐apoptotic, and anti‐inflammatory bioactivities. Consequently, the current study tested the hypothesis that SIM confers neuroprotection in a rodent model of depressive‐like phenotypes induced by Doxorubicin (DOX)/Cyclophosphamide (CP) polychemotherapy. Rats were divided into four cohorts (
n
= 10 per group). Control; SIM‐alone; chemotherapy; SIM/chemotherapy combination. SIM co‐treatment significantly improved depression‐like 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‐inflammation and oxidative stress vs the chemotherapy‐combination group. Concurrently, SIM reduced hippocampal oxidative stress (51% decrease in MDA) and inflammation (70% and 42% decrease in TNF‐α and NF‐κB). SIM also attenuated apoptosis (29% reduction in active caspase‐3). 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‐administration 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‐associated depression. Nevertheless, further investigation is warranted to fully elucidate the underlying antidepressant mechanisms of statins and to validate their clinical efficacy.