# Sacubitril/valsartan fails to prevent doxorubicin-induced cognitive impairment and hippocampal oxidative, inflammatory, and apoptotic alterations in rats

## TL;DR

This study found that sacubitril/valsartan does not protect against doxorubicin-induced brain damage and cognitive issues in rats.

## Contribution

The study reveals that sacubitril/valsartan's neuroprotective potential differs from its cardioprotective effects.

## Key findings

- Co-administration of VS and DOX did not reduce hippocampal oxidative, inflammatory, or apoptotic damage.
- VS failed to improve cognitive performance or mitigate neuroinjury in DOX-treated rats.
- Histopathological damage in DOX + VS-treated rats was comparable to DOX alone.

## Abstract

Doxorubicin (DOX) is a chemotherapeutic agent known for its effectiveness in treating various cancers. However, its clinical applicability is constrained by its neurotoxicity. DOX-induced toxicity is primarily driven by oxidative stress, inflammation, and mitochondrial dysfunction, resulting in elevated ROS and MDA, increased pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and NF-κB, and increased apoptotic activity, including caspase-3 and BAX. Sacubitril/Valsartan (VS), a dual neprilysin inhibitor and angiotensin receptor blocker used in heart failure management, has shown protective effects by ameliorating inflammation and oxidative stress. This study aimed to investigate the potential of VS to mitigate or prevent hippocampal damage in rats.

Forty male Wistar rats were randomly categorized into four groups (n = 10 per group): Control (normal saline), DOX (2.5 mg/kg), VS (60 mg/kg), and DOX + VS. VS was administered orally once daily via oral gavage, whereas DOX was delivered intraperitoneally weekly for 4 weeks. Body weight and survival were monitored daily. Cognitive performance was assessed using behavioral tests, followed by biochemical and histological analyses. Thereafter, oxidative, inflammatory, and pro-apoptotic markers were quantified.

DOX and VS co-administration resulted in significant reductions in body weight and survival compared with VS-treatment alone and controls. Furthermore, both DOX treatment alone and its co-administration with VS significantly increased hippocampal levels of oxidative, inflammatory, and apoptotic markers compared with VS treatment alone and controls. In addition, histopathological analysis revealed that hippocampal tissues subjected to DOX + VS treatment exhibited severe damage, comparable to that observed in tissues treated with DOX alone. In contrast, tissues treated with VS alone and controls showed less severe damage.

Combining VS with DOX did not significantly enhance spatial learning and working memory compared with DOX alone, nor did it mitigate neuroinjury. These findings suggest that VS is not a viable therapeutic agent for alleviating DOX-induced neurotoxicity and cognitive dysfunction. This research offers novel insight for the field of pharmacological discovery by demonstrating that the neuroprotective potential of neprilysin inhibition (a key mechanism of VS) differs significantly from its cardioprotective actions. Our findings provide a foundational basis for the design of future neuroprotective therapies and for further research.

Diagram depicting a scientific experiment on rats. It includes NOR and Y-Maze tests for behavioral assessment, images of brain tissue samples, a depiction of ELISA tests, and centrifugation for tissue analysis. The infographic shows treatments with either normal saline or sacubitril-valsartan. Key focus includes rat hippocampal tissue analysis for reactive oxygen species and inflammation markers, highlighting oxidative stress, neuroinflammation, and apoptosis.