Protective Effect of Avenanthramide-C on Auditory Hair Cells against Oxidative Stress, Inflammatory Cytokines, and DNA Damage in Cisplatin-Induced Ototoxicity

Abstract

Cisplatin-induced ototoxicity leads to hearing impairment, possibly through reactive oxygen species (ROS) production and DNA damage in cochlear hair cells (HC), although the exact mechanism is unknown. Avenanthramide-C (AVN-C), a natural, potent antioxidant, was evaluated in three study groups of normal adult C57Bl/6 mice (control, cisplatin, and AVN-C+cisplatin) for the prevention of cisplatin-induced hearing loss. Auditory brainstem responses and immunohistochemistry of outer hair cells (OHCs) were ascertained. Cell survival, ROS production, Phospho-H2AX-enabled tracking of DNA damage-repair kinetics, and expression levels of inflammatory cytokines (TNF-α, IL-1β, IL6, iNOS, and COX2) were assessed using House Ear Institute-Organ of Corti 1 (HEI-OC1 Cells). In the in vivo mouse model, following cisplatin-induced damage, AVN-C decreased the hearing thresholds and sheltered all cochlear turns’ OHCs. In HEI-OC1 cells, AVN-C preserved cell viability and decreased ROS production, whereas cisplatin enhanced both ROS levels and cell viability. In HEI-OC1 cells, AVN-C downregulated IL6, IL-1β, TNF-α, iNOS, and COX2 production that was upregulated by cisplatin treatment. AVN-C attenuated the cisplatin-enhanced nuclear H2AX activation. AVN-C had a strong protective effect against cisplatin-induced ototoxicity through inhibition of ROS and inflammatory cytokine production and DNA damage and is thus a promising candidate for preventing cisplatin-induced sensorineural hearing loss.

Effects of Nutraceuticals on Cisplatin-Induced Cytotoxicity in HEI-OC1 Cells

“…Cisplatin-induced damage in cochlear cells is mainly due to the production of ROS and the release of the proinflammatory molecules TNFα and IL-6 [39][40][41], leading to cellular death by apoptosis, necrosis [2], autophagy [10] and ferroptosis [42]. Much effort has been dedicated to finding substances capable of reverting ototoxicity, but at the moment none has been approved [43].…”

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions

“…The polyphenol curcumin reduced cisplatin-induced hearing loss and suppressed NF-κB-related inflammation pathways in the cochlea while providing optimal chemosensitivity [141,142]. Recently, treatment with avenanthramide-C (AVN-C), a potent naturally occurring polyphenolic compound found exclusively in oats, reduced ROS production, enhanced the survival of OHCs and inner hair cell (IHC) presynaptic ribbons, and protected against cisplatin-induced hearing loss in mice [143]. When administered to a mouse auditory HEI-OC1 cell line prior to cisplatin exposure, AVN-C significantly reduced ROS production and mitigated cisplatin-induced inflammation by reducing the expression of the pro-inflammatory mediators, IL-6, IL-1β, TNF-α, iNOS, and COX2 [143].…”

“…Recently, treatment with avenanthramide-C (AVN-C), a potent naturally occurring polyphenolic compound found exclusively in oats, reduced ROS production, enhanced the survival of OHCs and inner hair cell (IHC) presynaptic ribbons, and protected against cisplatin-induced hearing loss in mice [143]. When administered to a mouse auditory HEI-OC1 cell line prior to cisplatin exposure, AVN-C significantly reduced ROS production and mitigated cisplatin-induced inflammation by reducing the expression of the pro-inflammatory mediators, IL-6, IL-1β, TNF-α, iNOS, and COX2 [143]. Observations from previous studies suggest that AVN-C decreases the secretion of pro-inflammatory cytokines by inhibiting both NF-κB activity and mast cell degranulation [144,145].…”