Key points are not available for this paper at this time.
Abdullah Obaid Alshammari,1 Maha A Aldubayan,1 Ahmad H Alwashmi,2 Ahmad H Alhowail1 1Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia; 2Department of Orthopedic Surgery, College of Medicine, Qassim University, Buraydah, Kingdom of Saudi ArabiaCorrespondence: Ahmad H Alhowail, Email aalhowail@qu.edu.saBackground: Chemotherapy-induced cognitive impairment (âchemobrainâ) is mechanistically linked to oxidative stress, neuroinflammation, and apoptotic pathway dysregulation. Angiotensin receptorâneprilysin inhibitors and angiotensin II type-1 receptor blockers, such as sacubitril/valsartan (VS), have demonstrated neuroprotective potential; however, their effects in cisplatin (CIS)-induced neurotoxicity models remain poorly characterized.Methods: Forty male Wistar rats were randomized into four groups: Control, CIS (5 mg/kg, i.p). VS alone (40 mg/kg/day in drinking water), and CIS+VS, receiving three doses over 7 days. Cognitive performance was assessed 24 hours after the final dose via the Y-maze and novel object recognition test (NORT). Survival and body weight were monitored throughout. Hippocampal levels of reactive oxygen species (ROS), malondialdehyde (MDA), TNF-α, IL-1β, IL-6, total NF-κB, BAX, and total caspase-3 were quantified by ELISA, complemented by histopathological analysis.Results: CIS produced dose-limiting toxicity, with 40% mortality and approximately 13% body weight loss over 8 days. The CIS+VS group exhibited greater toxicity, with 50% mortality and approximately 16% weight loss, while the control and VS animals gained weight. Both CIS and CIS+VS groups demonstrated significant impairment in spatial and recognition memory, as reflected by reduced novel-arm entries and time spent in the Y-maze, and diminished novel object exploration in NORT relative to controls. Hippocampal oxidative stress, neuroinflammatory, and apoptosis-related signaling markers were markedly elevated following CIS and remained comparably elevated in the CIS+VS group, consistent with persistent neuroinflammation. Histopathological examination confirmed severe hippocampal tissue damage in both CIS-treated groups, with no attenuation observed in the CIS+VS group.Conclusion: CIS induces significant cognitive deficits accompanied by elevated neurotoxicity markers. Under the tested dosing schedule, adjunctive VS failed to rescue cognitive function or attenuate hippocampal neuro-injury. These findings reinforce oxidative stress, neuroinflammation, and apoptotic signaling as key mechanistic drivers of chemobrain and indicate that VS confers no neuroprotective benefit in this model. The experiment involves 40 Wistar rats divided into four groups: Control, CIS (5 mg/kg, i.p., 3 doses), VS alone (40 mg/kg/day, water) and CIS+VS. Dosing occurs from Day 0 to Day 5. Assessments include Y-Maze for spatial memory on Day 8, NORT for recognition memory on Day 9 and hippocampal tissue extraction on Day 10. Results show systemic toxicity with survival rates and body weight changes. Control and VS groups gain weight, while CIS and CIS+VS groups lose 13-16% weight. Cognitive tests reveal impairment in CIS and CIS+VS groups. Hippocampal markers indicate oxidative stress, neuroinflammation and apoptotic signaling, with severe tissue damage. Conclusion: CIS-induced neurotoxicity (âChemobrainâ) is driven by oxidative stress, neuroinflammation and apoptosis. Sacubitril/valsartan (VS) did not improve cognitive function or reduce neuro-injury in this dosing schedule.A flowchart detailing an experimental design with results on CIS-induced neurotoxicity in Wistar rats.Keywords: cisplatin, sacubitril, valsartan, cognitive impairment, oxidative stress, inflammation, apoptosis-related signaling
Alshammari et al. (Mon,) studied this question.