Abstract
Background:Cisplatin is an alkylating agent that inhibits DNA replication and interferes with proliferation of cancer cells. However, the major limiting factor for its use is the possible development of adverse effects, including ototoxicity. Up till now, the mechanisms of this ototoxicity remain poorly understood. However, induction of oxidative stress and activation of the inflammatory cascade were suggested as contributing factors. Purpose:The aim of this study was to explore the effect of L-arginine on cisplatin-induced ototoxicity in rats. Methods:Thirty male adult Wistar rats were divided into three equal groups as follows: control group; cisplatin group and cisplatin + L-arginine group. Auditory brainstem response (ABR), tissue oxidative stress parameters, total nitrate/nitrite, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) content, transforming growth factor beta 1 (TGF-β1), tumor necrosis factor alpha (TNF-α) and interleukin 15 (IL-15) were assessed. Also, the cochlear tissues were subjected to histopathological and electron microscopic examination. Results:Administration of L-arginine to cisplatin-treated rats induced significant decrease in the average ABR threshold shifts at all frequencies, tissue TGF-β1, TNF-α and IL-15 associated with significant increase in tissue antioxidant enzymes, total nitrate/nitrite and Nrf2/HO-1 content compared to cisplatin group. Also, pretreatment of cisplatin-injected rats with L-arginine induced significant improvement of the histopathological and electron microscopic picture compared to cisplatin group. Conclusion:L-arginine may serve as a promising therapeutic modality for amelioration of cisplatin-induced ototoxicity.
Highlights
Cisplatin is one of the platinum-containing chemotherapeutic agents that are widely used for the treatment of various types of malignancies including testicular, ovarian, breast and bladder carcinoma (Dasari and Tchounwou, 2014)
Administration of L-arginine to cisplatin-treated rats induced significant decrease in the average Auditory brainstem response (ABR) threshold shifts at all frequencies, tissue TGF-β1, TNF-α and interleukin 15 (IL-15) associated with significant increase in tissue antioxidant enzymes, total nitrate/nitrite and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) content compared to cisplatin group
L-arginine may serve as a promising therapeutic modality for amelioration of cisplatin-induced ototoxicity
Summary
Cisplatin is one of the platinum-containing chemotherapeutic agents that are widely used for the treatment of various types of malignancies including testicular, ovarian, breast and bladder carcinoma (Dasari and Tchounwou, 2014). Cisplatin administration usually leads to loss of the inner and outer hair cells together with irreversible damage of the spiral ganglion neurons resulting in irreversible hearing loss (Sheth et al, 2017). These harmful effects may be attributed to induction of oxidative stress with increased production of reactive oxygen species (ROS) together with affection of the inflammatory cascade which were proven to play an important role in the cochlear damage induced by cisplatin (Rybak et al, 2019). An early increase in the expression of TGF-β1 was reported during cochlear damage induced by aminoglycosides followed by down-regulation as the inflammatory response resolves. Conclusion: L-arginine may serve as a promising therapeutic modality for amelioration of cisplatin-induced ototoxicity
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