The Ameliorative Effect of JNK Inhibitor D-JNKI-1 on Neomycin-Induced Apoptosis in HEI-OC1 Cells.

Junling Zhao,Zhiwei Huang,Ruiming Yang,Liang Gong,Hao Liu

doi:10.3389/fnmol.2022.824762

Abstract

Aminoglycosides can cause ototoxicity and lead to hair cell damage. Neomycin-induced ototoxicity is related to increased production of reactive oxygen species (ROS) and triggering hair cell apoptosis. The c-Jun-N-terminal kinase (JNK) pathway plays an essential role during hair cell damage. This study was designed to investigate an inhibitor of JNK, D-JNKI-1 (AM-111/brimapitide) in neomycin-induced HEI-OC1 cell apoptosis. The results demonstrate that neomycin increased intracellular ROS accumulation, which induces apoptosis. D-JNKI-1 decreased neomycin-induced ROS generation, reduced caspase-8 and cleavage of caspase-3 expression, sustained JNK activation and AMPK and p38 phosphorylation, downregulated Bax, and upregulated Bcl-2. Together, D-JNKI-1 plays an essential role in protecting against neomycin-induced HEI-OC1 cell apoptosis by suppressing ROS generation, which inhibited JNK activation and AMPK and p38 phosphorylation to ameliorate JNK-mediated HEI-OC1 cell apoptosis.

Highlights

Aminoglycosides cause ototoxicity in the inner ear, resulting in hair cell death and causes permanent hearing loss
The results show that the percentage of cell death and survival were not affected by D-JNKI-1 treatment compared to the normal control group, and the percentage of survival House Ear Institute-Organ of Corti 1 (HEI-OC1) cells was significantly decreased after neomycin exposure and increased with neomycin and D-JNKI1 treatment simultaneously (Figure 4A)
Aminoglycosides induce hair cell oxidative stress; reactive oxygen species (ROS) levels in hair cells exposed to neomycin revealed the aminoglycosideinduced ototoxicity in hair cells and ROS accumulation in hair cells leads to cell death

Summary

Introduction

Aminoglycosides cause ototoxicity in the inner ear, resulting in hair cell death and causes permanent hearing loss. Aminoglycosides induce highly toxic reactive oxygen species (ROS) in the hair cell region and cause hair cell damage (Nadol, 1993). The mechanism of aminoglycoside-induced hair cell damage involves free radical formation and hair cell oxidative stress (Huang et al, 2000) and apoptotic cell death pathways. The ROS-initiated hair cell death includes caspase-dependent and caspase-independent apoptosis and necrosis (Chan, 2005; Genestra, 2007). Mitochondrial ROS formation induces the mitochondrial permeability transition pore (PTP) and causes the inner membrane to become permeable to small molecules that lead to apoptosis (Murphy, 2009). Evidence has shown that hair cell apoptosis is the predominant mechanism in aminoglycoside-induced ototoxicity (Huth et al, 2011)

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Results

Conclusion