Naunyn-Schmiedeberg's archives of pharmacology · 2025
Mechanistic insights into the hepatoprotective role of rabeprazole against cyclophosphamide-induced hepatotoxicity via AMPK/SIRT1 activation and suppression of TLR4/NF-κB and MAPK pathways.
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Saleh Asmaa, Raslan Nahed A, Selim Heba Mohammed Refat M, Ibrahim Samar, Farghly Ahmed Mohamed, Shalkami Abdel-Gawad S, Salama Lamiaa A, Elhusseiny Shaza M, Hafez Shaimaa M, Mahmoud Nihal A, Alwakeel Asmaa I, Ali Shimaa O, Elsabbagh Sherif A, Fouda Manar Seleem, El-Dessouki Ahmed M
Аннотация
AIMS: This study evaluates the ability of Rabeprazole (RAB) in counteracting cyclophosphamide (CP)-induced hepatotoxicity, focusing on its regulatory impact on key molecular signaling pathways, particularly AMPK/SIRT1, PI3K/Akt, TLR4/NF-κB, and MAPK, as well as its influence on NLRP3 inflammasome activation.
MAIN METHODS: Rats were assigned into four distinct groups (n = 8 each): a control group administered distilled water; a CP group administered a single intraperitoneal dose of CP (200 mg/kg) on the seventh day; and two treatment groups pretreated orally with RAB (10 or 30 mg/kg/day) for ten days, with CP delivered on day 7. Biochemical, histological, immuno-histochemical, qRT-PCR, and western blotting procedures were conducted to evaluate liver function, oxidative status, and molecular signaling.
KEY FINDINGS: Rats exposed to CP showed marked increases in hepatic markers (ALT, AST), together with decreases in antioxidative markers (GSH, Nrf2, HO-1) and increases in MDA, MPO, iNOS, as well as pro-inflammatory markers represented by IL-6, TNF-α, IL-1β. Hepatic expression of AMPK, SIRT1, and PI3K/Akt was markedly suppressed, while TLR4, NF-κB p65, MAPK proteins, and NLRP3 were upregulated. RAB pretreatment dose-dependently restored hepatic enzyme levels, corrected redox imbalance, reduced cytokine release, and normalized gene and protein expression profiles. Histopathological improvements further corroborated the protective effect of RAB.
SIGNIFICANCE: These results indicate that Rabeprazole may serve as an effective therapeutic option to reduce CP-induced liver injury through its multifaceted protective actions, highlighting the necessity for more extensive research in subsequent studies.
MAIN METHODS: Rats were assigned into four distinct groups (n = 8 each): a control group administered distilled water; a CP group administered a single intraperitoneal dose of CP (200 mg/kg) on the seventh day; and two treatment groups pretreated orally with RAB (10 or 30 mg/kg/day) for ten days, with CP delivered on day 7. Biochemical, histological, immuno-histochemical, qRT-PCR, and western blotting procedures were conducted to evaluate liver function, oxidative status, and molecular signaling.
KEY FINDINGS: Rats exposed to CP showed marked increases in hepatic markers (ALT, AST), together with decreases in antioxidative markers (GSH, Nrf2, HO-1) and increases in MDA, MPO, iNOS, as well as pro-inflammatory markers represented by IL-6, TNF-α, IL-1β. Hepatic expression of AMPK, SIRT1, and PI3K/Akt was markedly suppressed, while TLR4, NF-κB p65, MAPK proteins, and NLRP3 were upregulated. RAB pretreatment dose-dependently restored hepatic enzyme levels, corrected redox imbalance, reduced cytokine release, and normalized gene and protein expression profiles. Histopathological improvements further corroborated the protective effect of RAB.
SIGNIFICANCE: These results indicate that Rabeprazole may serve as an effective therapeutic option to reduce CP-induced liver injury through its multifaceted protective actions, highlighting the necessity for more extensive research in subsequent studies.