Abstract
Eupatilin (5,7-dihydroxy-3′,4′,6-trimethoxyflavone) is a pharmacologically active flavone that has been isolated from a variety of medicinal plants and possesses a number of pharmacological properties. This study evaluates the antioxidant and antiapoptotic effects of eupatilin on cisplatin-induced ototoxicity using in vitro and in vivo models including HEI-OC1 cells, cochlear hair cells, and zebrafish. Employing a CCK8 assay and Annexin V-FITC/PI double staining, we found that eupatilin significantly alleviated cisplatin-induced apoptosis and increased hair cell viability. The level of reactive oxygen species (ROS) was evaluated by CellROX green and MitoSOX Red staining. The results showed that eupatilin possesses antioxidant activity. MitoTracker Red staining indicated that eupatilin remarkably decreased mitochondrial damage. Furthermore, we demonstrated that eupatilin protects hair cells from cisplatin-induced damage. Mechanistic studies in cisplatin-induced HEI-OC1 cells revealed that eupatilin promoted Bcl-2 expression, downregulated Bax expression, reversed the increase in caspase-3 and PARP activity, and reduced the expression of phosphorylated p38 and JNK. Our data suggest a novel role for eupatilin as a protective agent against ototoxic drug-induced hair cell apoptosis by inhibiting ROS generation and modulating mitochondrial-related apoptosis.
Highlights
At least 700 million people worldwide suffer from sensorineural hearing loss caused by ototoxic antibiotics, noise, chemotherapy, and aging [1]
House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were derived from the immortalized cell line of the mouse organ of Corti, which is sensitive to ototoxic drugs including aminoglycosides and cisplatin
HEI-OC1 cells were treated with cisplatin at the dose and time conditions indicated in Figure 1(a) to establish an in vitro ototoxicity model. 30 μM cisplatin was chosen as the optimal concentration for further studies
Summary
At least 700 million people worldwide suffer from sensorineural hearing loss caused by ototoxic antibiotics, noise, chemotherapy, and aging [1]. There are currently no pharmacological agents aimed at preventing or treating sensorineural hearing loss that have been approved by the Food and Drug Administration (FDA). Drug-induced hearing loss is defined as a hearing impairment whose onset occurs when therapeutic drugs damage the auditory system as a side effect. More than 600 drugs have been identified to possess ototoxic properties. Aminoglycoside antibiotics and platinum-containing chemotherapy drugs are the most investigated. Cisplatin- (Cis-) induced hearing loss, mainly in the high-frequency range, is bilateral and permanent which adversely affects the quality of life of cancer patients
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