Simvastatin Mitigates Chemotherapy-Induced Depressive-Like Behaviors in Rats

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.