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.
Highlights
Methotrexate (MTX) is a chemotherapeutic agent that has been used in clinical practice since the 1950s
The paeonol alone group showed no significant difference in the testicular weight compared to the control group
The serum testosterone level significantly decreased in MTX-intoxicated rats, while paeonol treatment significantly increased the testosterone level compared to the MTX group (Table 1)
Summary
Methotrexate (MTX) is a chemotherapeutic agent that has been used in clinical practice since the 1950s. Inhibition of dihydrofolate reductase by MTX results in suppression of purine and pyrimidine nucleotide production, and subsequently, inhibition of DNA and RNA synthesis, especially in rapidly dividing malignant cells [1,2]. The cytotoxic effects of MTX are not limited to malignant cells but can affect normal cells in different organs [3,4,5], including the testis [6,7]. Inflammation, and apoptosis may account for MTX-induced cellular damage [5,6]. The exact mechanisms responsible for MTX-induced testicular damage are yet to be fully elucidated. Besides the disruption of the blood–testis barrier, MTX can affect the reproductive capacity via suppression of the cellular proliferation of germinal and non-germinal (Sertoli and Leydig cells) elements of the seminiferous tubules [9]
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