Amlodipine protects against methotrexate nephrotoxicity by modulating inflammation, oxidative stress, and apoptosis through NF-κB/PPAR-β/caspase 3 pathways

Shahid Karim; Dina Kutbi; Huda Alkreathy; Basma Alharthy; Mohammed Alsieni; Hussam Daghistani; Ohoud Hassan Shakroun; Mohammed Bazuhair; Mohammed Omar Barasheed; Ahmed Shaker Ali

doi:10.51847/niC6BprrEv

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Amlodipine protects against methotrexate nephrotoxicity by modulating inflammation, oxidative stress, and apoptosis through NF-κB/PPAR-β/caspase 3 pathways

Shahid Karim^*✉ , Dina Kutbi , Huda Alkreathy , Basma Alharthy , Mohammed Alsieni , Hussam Daghistani , Ohoud Hassan Shakroun , Mohammed Bazuhair , Mohammed Omar Barasheed , Ahmed Shaker Ali

Abstract

Methotrexate (MTX), a folic acid antagonist used for treating malignancies and autoimmune disorders, has limited use due to its toxicity, including bone marrow suppression and hepatic and renal damage. High doses of MTX (>500 mg/m²) are particularly harmful. Calcium channel blockers, such as amlodipine, may alleviate MTX-induced toxicity. This study investigated amlodipine’s potential to protect against MTX-induced acute kidney injury in rats. Thirty-two male Wistar rats were divided into four groups: a control group receiving saline, a group treated with MTX alone, and two groups receiving MTX followed by oral amlodipine at doses of 5 mg/kg or 10 mg/kg. Serum levels of kidney function biomarkers (urea, creatinine, uric acid, albumin, KIM-1, NGAL), inflammatory markers (ICAM-1, VCAM-1, IL-6, TNF-α), and oxidative stress markers (SOD, GSH, TBARS) were measured. Histopathological and immunohistochemical analyses were also performed. MTX increased serum levels of kidney function biomarkers and decreased glomerular filtration rate (GFR), which were significantly improved by amlodipine treatment. Amlodipine also reversed increases in inflammatory markers and the expression of NFκB and Caspase-3, while normalizing PPARβ levels. Histopathological findings supported these results. Thus, amlodipine demonstrates nephroprotective effects and may be a viable intervention for MTX-induced acute kidney injury‎.

Keywords: Methotrexate, Amlodipine, NF kB, Acute kidney injury, Caspase 3

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Karim S, Kutbi D, Alkreathy H, Alharthy B, Alsieni M, Daghistani H, et al. Amlodipine protects against methotrexate nephrotoxicity by modulating inflammation, oxidative stress, and apoptosis through NF-κB/PPAR-β/caspase 3 pathways. J Adv Pharm Educ Res. 2024;14(4):7-17. https://doi.org/10.51847/niC6BprrEv

APA

Karim, S., Kutbi, D., Alkreathy, H., Alharthy, B., Alsieni, M., Daghistani, H., Shakroun, O. H., Bazuhair, M., Barasheed, M. O., & Ali, A. S. (2024). Amlodipine protects against methotrexate nephrotoxicity by modulating inflammation, oxidative stress, and apoptosis through NF-κB/PPAR-β/caspase 3 pathways. Journal of Advanced Pharmacy Education and Research, 14(4), 7-17. https://doi.org/10.51847/niC6BprrEv