Efficiency of antioxidant Avenanthramide-C on high-dose methotrexate-induced ototoxicity in mice

Abstract

Methotrexate (MTX) has been used in treating various types of cancers but can also cause damage to normal organs and cell types. Folinic acid (FA) is a well-known MTX antidote that protects against toxicity caused by the drug and has been used for decades. Since hearing loss caused by MTX treatment is not well studied, herein we aimed to investigate the efficiency of the antioxidant Avenanthramide-C (AVN-C) on high-dose MTX (HDMTX) toxicity in the ear and provide insights into the possible mechanism involved in MTX-induced hearing loss in normal adult C57Bl/6 mice and HEI-OC1 cells. Our results show that the levels of MTX increased in the serum and perilymph 30 minutes after systemic administration. MTX increased hearing thresholds in mice, whereas AVN-C and FA preserved hearing within the normal range. MTX also caused a decrease in wave I amplitude, while AVN-C and FA maintained it at higher levels. MTX considerably damaged the cochlear synapses and neuronal integrity, and both AVN-C and FA rescued the synapses. MTX reduced the cell viability and increased the reactive oxygen species (ROS) level in HEI-OC1 cells, but AVN-C and FA reversed these changes. Apoptosis- and ROS-related genes were significantly upregulated in MTX-treated HEI-OC1 cells; however, they were downregulated by AVN-C and FA treatment. We show that MTX can cause severe hearing loss; it can cross the blood–labyrinth barrier and cause damage to the cochlear neurons and outer hair cells (OHCs). The antioxidant AVN-C exerts a strong protective effect against MTX-induced ototoxicity and preserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage. The mechanism of AVN-C against MTX suggests that ROS is involved in HDMTX-induced ototoxicity.

Is Methotrexate Ototoxic? Investigating the Ototoxic Late Effects of Pediatric Cancer Treatment

“…Most patients who were treated with known ototoxic cancer therapy received baseline hearing evaluations (i.e., cisplatin, carboplatin). Although MTX ototoxicity has been documented in mice, it is not a recognized ototoxic agent in humans ( Mateos et al, 2022 ; Umugire et al, 2022 ). Therefore, many of the patients with leukemia and osteosarcoma who were treated with MTX did not have baseline audiology exams.…”

“…Recently, Umugire et al (2022) demonstrated that MTX can cause severe hearing loss in mice by crossing the blood–labyrinth barrier and damaging neurons and OHCs of the cochlea. Furthermore, this group showed that the antioxidant Avenanthramide C created a strong protective effect against high-dose MTX-induced ototoxicity in mice and conserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage ( Umugire et al, 2022 ). Thus, further clinical, gene expression, molecular, and biochemical studies are warranted to determine its ototoxic and neurotoxic effects in humans and to develop appropriate therapies.…”

“…Although the late effects of MTX treatment have been recognized for years, the mechanism of its pediatric neurotoxicity is not well understood ( Daetwyler et al, 2022 ). Animal model studies using mice have revealed a decrease in myelin sheath thickness in the white matter of MTX-treated mice and depletion of oligodendrocyte lineage cells compared to controls ( Gibson et al, 2019 ; Mateos et al, 2022 ; Umugire et al, 2022 ). The ototoxicity of MTX has not been well described in humans; however, it has been demonstrated to cause hearing loss in mice by crossing the blood–labyrinth barrier and damaging cochlear neurons and outer hair cells (OHCs; Mateos et al, 2022 ; Umugire et al, 2022 ).…”