Amelioration of Cisplatin-Induced Ototoxicity in Rats by L-arginine: The Role of Nitric Oxide, Transforming Growth Factor Beta 1 and Nrf2/HO-1 Pathway

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.

Protective Role of Darbepoetin in Cisplatin-Induced Ototoxicity

“…Similar to the results of our study, in a study examining the effects of L-arginine against CDDP-induced ototoxicity, it was found that besides a decrease in TNF-α levels, an increase in antioxidant levels and an increase in Nrf2/HO-1 (25).…”

An insight into role of amino acids as antioxidants via NRF2 activation

“…Similarly, arginine activates NRF2 and upregulates the expression of the phase II metabolizing and antioxidative enzymes, thereby protecting ovine intestinal epithelial cells from LPS-induced cell death and oxidative damage (Zhang et al 2019 ). It also attenuates cisplatin–induced ototoxicity via the activation of the NRF2/HO-1 pathway among others in rats (Estfanous et al 2020 ).…”