AUTHOR=Morsy Mohamed A. , El-Sheikh Azza A. K. , Abdel-Hafez Sara Mohamed Naguib , Kandeel Mahmoud , Abdel-Gaber Seham A. 

TITLE=Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.774387

DOI=10.3389/fphar.2022.774387

ISSN=1663-9812

ABSTRACT=Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side ‎effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, ‎can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was ‎given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared ‎to control, MTX caused nephrotoxic effects manifested by increased serum urea and ‎creatinine, and distortion in renal histological architecture, with significant increase in ‎mean glomerular diameter and up-regulation of kidney injury molecule-1. MTX caused ‎oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase ‎while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation ‎by up-regulating TLR4, NF-κB and IL-1β and caused apoptosis by induction of caspase 3. ‎Administering paeonol with MTX improved kidney functional and structural parameters, ‎as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both ‎MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein ‎‎(P-gp) that helps in MTX elimination, and their drug combination further up-regulated ‎renal P-gp. In silico, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting ‎that its effect on P-gp is not on functional, but on expression level. In vitro, the cytotoxic ‎effects of paeonol and/or MTX were tested on colon cancer cells and showed similar ‎cytotoxicity of both drugs separately, and that their combination had an almost additive ‎cytotoxic effect. In conclusion, paeonol protects against MTX-induced nephrotoxicity ‎through antioxidant, anti-inflammatory and anti-apoptotic mechanisms and might ‎potentiate MTX chemotherapeutic efficacy.‎