Piracetam mitigates nephrotoxicity induced by cisplatin via the AMPK-mediated PI3K/Akt and MAPK/JNK/ERK signaling pathways.

Autor: El-Dessouki AM; Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 12566, Giza, Egypt., Alzokaky AA; Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; Pharmacology and Biochemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt., Raslan NA; Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; Clinical Pharmacy Program, College of Health Sciences and Nursing, Al-Rayan Colleges, Madina, Saudi Arabia., Ibrahim S; Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Galala University, Ataka, Egypt., Salama LA; Department of Microbiology and Immunology, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt., Yousef EH; Pharmacology and Biochemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt. Electronic address: Ehamdy@horus.edu.eg.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Aug 20; Vol. 137, pp. 112511. Date of Electronic Publication: 2024 Jun 22.
DOI: 10.1016/j.intimp.2024.112511
Abstrakt: Aims: Cisplatin (CDDP) is commonly employed as an antineoplastic agent, but its use is significantly limited by the occurrence of dose-dependent nephrotoxicity, the detailed mechanisms of which remain unclear. This research is aimed to explore the molecular mechanisms of Piracetam (PIR)'s protective effects on nephrotoxicity resulting from CDDP exposure and to elucidate the mechanisms responsible for these effects.
Main Methods: PIR was given in dosages of 100 and 300 mg/kg body weight for a duration of 15 days; concurrently, on the last day, a single 10 mg/kg dose of CDDP was delivered via intraperitoneal injection. Forty-eight hours post-CDDP injection, the animals were sacrificed to assess nephrotoxicity. Blood samples and renal tissues were taken for biochemical and histopathological investigations. Serum creatinine and blood urea nitrogen (BUN) were measured. AMP-activated protein kinase (AMPK), caspase-9 and nuclear factor kappa b p65 (NF-κB p65) were assessed by immunohistochemistry method. Enzyme-linked immunosorbent assay (ELISA) analysis was employed to determine cytochrome c (Cyt. c), Bcl-2-associated X-protein (BAX), caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO), and interleukin-1β (IL-1β) levels in renal tissue homogenates. The mRNA levels of tumor protein P53 (TP53), phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinases (JNK) were tested by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, histopathological evaluations of the renal tissues and the binding affinity of PIR to AMPK by molecular docking were also performed.
Key Findings: Pre-treatment with PIR enhanced renal function markers such as urea and creatinine, mitigated histological damage, and diminished inflammatory cell presence in renal tubules. PIR demonstrated antioxidant effects by reestablishing the equilibrium between pro-oxidants and antioxidants such as MPO, HO-1, Nrf2, as well as SOD. Furthermore, PIR inhibited the inflammatory pathways through the MAPK/NF-κB pathway. Additionally, PIR counteracted the CDDP-induced decline in PI3K/Akt activity and hindered caspase-dependent apoptotic processes.
Significance: In summary, PIR appears to be an effective therapeutic strategy for reducing CDDP-induced nephrotoxicity, attributed to its antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Consequently, PIR may serve as a complementary treatment alongside CDDP to alleviate nephrotoxicity associated with CDDP.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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