Agmatine Alleviates Cisplatin-Induced Ototoxicity by Activating PI3K/AKT Signaling Pathway.

Ying Zhang,Zhe Lv,Qiang He

doi:10.1523/eneuro.0434-21.2022

Abstract

Cisplatin-induced ototoxicity can be partially attributed to excessive reactive oxygen species (ROS) production, and agmatine is well-known for the activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit ROS production. Whether agmatine could be used to alleviate cisplatin-induced ototoxicity is investigated. Cisplatin-exposed House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants showed increased ROS production detected by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining and decreased cell viability detected by Cell Counting Kit-8 (CCK-8) or Myosin 7a staining, which could be reversed by the agmatine pretreatment. Cisplatin intraperitoneally injected C57BL/6 mice demonstrated damaged auditory function as indicated by distortion products otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) assays, and trans-tympanically administrated agmatine in the left ears could partly prevent the auditory function loss. Mechanistically, downregulated B-cell lymphoma 2 (Bcl-2) expression, upregulated Bcl2-associated x (Bax) expression, and diminished p-PI3K and p-AKT expression were detected in cisplatin-exposed HEI-OC1 cells and cochlear explants, which could be prevented by the pretreatment with agmatine. Our investigation demonstrates that agmatine pretreatment could alleviate cisplatin-induced ototoxicity with the activation of PI3K/AKT signaling pathway.

Highlights

Cisplatin was approved in 1978 by the US Food and Drug Administration (FDA) to treat ovarian cancer and metastatic testicular patients(Farrell 2015)
It is generally believed that cisplatin-induced ototoxicity may be attributed to the excessive reactive oxygen species (ROS) production by the cochlea (Yu, Gu et al 2020), and endoplasmic reticulum stress is a target for treatment of hearing loss
Only 200 μM agmatine could diminish the viability of House Ear Institute-Organ of Corti 1 (HEI-OC1) cells (Figure 1b), which indicated that the dose under 200 μM was safe

Summary

Introduction

Cisplatin was approved in 1978 by the US Food and Drug Administration (FDA) to treat ovarian cancer and metastatic testicular patients(Farrell 2015). The incidence of cisplatin-induced ototoxicity can range from twenty percent to seventy percent, which may manifest with progressive, irreversible, and bilateral hearing loss (Tang, Wang et al 2021). Young children are more inclined to cisplatin-induced ototoxicity with delayed speech development and psychosocial and cognitive development (Knight, Kraemer et al 2005, Rybak, Mukherjea et al 2019). It is generally believed that cisplatin-induced ototoxicity may be attributed to the excessive reactive oxygen species (ROS) production by the cochlea (Yu, Gu et al 2020), and endoplasmic reticulum stress is a target for treatment of hearing loss (Wang and Xu. 2020). Multiple promisings strategies have been performed to alleviate, treat, and prevent cisplatin-induced ototoxicity, and none of these strategies has been confirmed or recommended by the FDA (Gentilin, Simoni et al 2019, Mukherjea, Dhukhwa et al.2020)

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