Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
Department of Companion Animal Health, College of Rehabilitation and Health, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
Free Radic Biol Med. 2023 Aug 1;204:177-183. doi: 10.1016/j.freeradbiomed.2023.04.017. Epub 2023 Apr 28.
Aminoglycoside, a medicinal category of antibiotics, are used in treatment of Gram-negative bacterial infections. Although they are the most widely-used antibiotics due to their high efficacy and low cost, several main adverse effects have been reported including nephrotoxicity and ototoxicity. Since drug-induced ototoxicity is one of the major etiological causes of acquired hearing loss, we examined cochlear hair cell damages caused by three aminoglycosides (amikacin, kanamycin, and gentamicin), and investigated protective property of an isoquinoline-type alkaloid, Berberine chloride (BC). Berberine, a well-known bioactive compound found from medicinal plants, has been known to have anti-inflammatory, antimicrobial effects. To determine protective effect of BC in aminoglycoside-induced ototoxicity, hair cell damages in aminoglycoside- and/or BC-treated hair cells using ex vivo organotypic culture system of mouse cochlea. Mitochondrial ROS levels and depolarization of mitochondrial membrane potential were analyzed, and TUNEL assay and immunostaining of cleaved caspase-3 were performed to detect apoptosis signals. As the results, it was found that BC significantly prevented aminoglycoside-induced hair cell loss and stereocilia degeneration by inhibiting excessive accumulation of mitochondrial ROS and subsequent loss of mitochondrial membrane potential. It eventually inhibited DNA fragmentation and caspase-3 activation, which were significant for all three aminoglycosides. This study is the first report suggested the preventative effect of BC against aminoglycoside-induced ototoxicity. Our data also suggests a possibility that BC has the potential to exert a protective effect against ototoxicity caused by various ototoxic drugs leading to cellular oxidative stress, not limited to aminoglycoside antibiotics.
氨基糖苷类是一类用于治疗革兰氏阴性菌感染的抗生素药物。尽管由于其高效、低成本而被广泛应用，但也报道了几种主要的不良反应，包括肾毒性和耳毒性。由于药物性耳毒性是获得性听力损失的主要病因之一，我们研究了三种氨基糖苷类药物（阿米卡星、卡那霉素和庆大霉素）引起的耳蜗毛细胞损伤，并研究了异喹啉型生物碱小檗碱（BC）的保护作用。小檗碱是一种从药用植物中提取的具有生物活性的化合物，已知具有抗炎、抗菌作用。为了确定 BC 在氨基糖苷类耳毒性中的保护作用，我们在体外鼠耳蜗器官型培养系统中研究了氨基糖苷类和/或 BC 处理的毛细胞中的毛细胞损伤。分析了线粒体 ROS 水平和线粒体膜电位去极化，并进行了 TUNEL 检测和裂解 caspase-3 的免疫染色，以检测凋亡信号。结果发现，BC 通过抑制线粒体 ROS 的过度积累和随后的线粒体膜电位丧失，显著防止了氨基糖苷类引起的毛细胞损失和静纤毛退化。它最终抑制了 DNA 片段化和 caspase-3 的激活，这对所有三种氨基糖苷类药物都是显著的。本研究首次报道了 BC 对氨基糖苷类耳毒性的预防作用。我们的数据还表明，BC 有可能对各种导致细胞氧化应激的耳毒性药物引起的耳毒性发挥保护作用，而不仅仅是氨基糖苷类抗生素。
