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Войти в исследования Drug design, development and therapy · 2026
Sacubitril/Valsartan Fails to Ameliorate Cisplatin-Induced Cognitive Impairment.
СтатьяНазвание и аннотация: Перевод в очереди
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Alshammari Abdullah Obaid, Aldubayan Maha A, Alwashmi Ahmad H, Alhowail Ahmad H
Аннотация
BACKGROUND: Chemotherapy-induced cognitive impairment ("chemobrain") is mechanistically linked to oxidative stress, neuroinflammation, and apoptotic pathway dysregulation. Angiotensin receptor-neprilysin 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.
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.