The Possible Contribution of P-Glycoprotein in the Protective Effect of Paeonol against Methotrexate-Induced Testicular Injury in Rats

Abstract

Paeonol, a phenolic ingredient in the genus Paeonia, possesses antioxidant and anti-inflammatory effects. Methotrexate (MTX) is a commonly used chemotherapeutic agent; however, its germ cell damage is a critical problem. P-glycoprotein (P-gp), an efflux transporter, is a member of the blood–testis barrier. The present study evaluated the protective effect of paeonol on MTX-induced testicular injury in rats with the exploration of its mechanism and the possible contribution of P-gp in such protection. Testicular weight, serum testosterone, and testicular P-gp levels were measured. Testicular oxidant/antioxidant status was evaluated via determining the levels of malondialdehyde, total nitrite, reduced glutathione, and superoxide dismutase activity. The inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the apoptotic marker caspase 3 were estimated immunohistochemically. Testicular histopathology and spermatogenesis scores were also examined. MTX caused histopathologically evident testicular damage with decreased testicular weight, testosterone level, and spermatogenesis score, as well as significant increases in oxidative, inflammatory, and apoptotic responses. Paeonol significantly restored testicular weight, testosterone level, spermatogenesis score, and oxidant/antioxidant balance. Moreover, paeonol increased the testicular P-gp level and significantly decreased TNF-α and caspase 3 immunostaining. In conclusion, paeonol offered a protective effect against MTX-induced testicular injury through its antioxidant, anti-inflammatory, and antiapoptotic effects, as well as by increasing testicular P-gp level.

Allopurinol and Febuxostat Equally Attenuate Methotrexate-Induced Testicular Injury In Rats Via Activation Of EGF/ ERK1/2/HO‐1 Signaling Pathway.

“…Caspase 3, is a crucial enzyme in programmed cell death pathway is implicated in germ cell apoptosis with MTX administration [27]. In current work, MTX-induced caspase-3 expression in testis, which agrees with [21] who reported that MTX-induced elevation in caspase 3 immunostaining. Induction of oxidative stress and in ammation are two supposed mechanisms induce apoptosis of testicular cells [28].…”

“…In current study, after administration of MTX, cellular TNF-α activity signi cantly increased. Many studies illustrate that, TNF-α has a role in the pathogenesis of MTX-induced testicular injury [21].…”

Mechanisms of Antidiabetic Activity of Methanolic Extract of Punica granatum Leaves in Nicotinamide/Streptozotocin-Induced Type 2 Diabetes in Rats

“…This suggests that the MEPGL may either enhance the production of GSH and/or may decrease the oxidative stress resulting in a reduction in GSH levels. The protection of GSH is by scavenging the free radicals, acting as a cofactor for antioxidant enzymes, and accelerating the xenobiotic detoxification [ 42 ]. GPx reacts with various lipid hydroperoxides that are generated during lipid peroxidation and it enhances the reduction of hydrogen peroxide in the presence of GSH to water.…”

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

“…Few in vitro studies have shown that paeonol might modulate the expression of efflux transporters that accept MTX as a substrate, such as BCRP and P-gp (Zhang et al, 2015). One recent in vivo study reported that paeonol could affect testicular expression levels of P-gp (Morsy et al, 2020a). Paeonol seems to act as an "adaptogen."…”