Berberine chloride protects cochlear hair cells from aminoglycoside-induced ototoxicity by reducing the accumulation of mitochondrial reactive oxygen species.

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.

Protective effects of nigella sativa oil against gentamicin-induced ototoxicity in rats: A dose-ranging study.

OBJECTIVE: Aminoglycosides are relatively potent antibiotics used against some life-threatening infections but contribute to ototoxicity. Although the beneficial effects of high-dose nigella sativa oil (NSO) on ototoxicity in the form of intratympanic or oral use have been demonstrated, no variable-dose studies have been conducted on this subject. We aimed to investigate the potential protective effect of different doses of intraperitoneal (i.p.) NSO on Gentamicin (GM)-induced ototoxicity with auditory brainstem responses (ABR) testing. METHODS: Thirty adult male Sprague-Dawley rats (300-400 gr) were used in this study. Rats were randomly divided into 5 groups, with six animals in each group: All the groups received GM (120 mg/kg i.p) for ten days. Group 1: 0.9% saline solution (0.3 ml/kg i.p.), Group 2: NSOL (low dose 0.1 ml/kg i.p.), Group 3: NSOM (median dose 0.3 ml/kg i.p.), Group 4: NSOH (high dose 3 ml/kg i.p.), Group 5: NSOML (late onset median dose 0.3 ml/kg i.p) were given for fifteen days. But death occurred in 3 rats in group 4 and they were excluded from the study. The pretreatment and posttreatment ABR testings were performed. RESULTS: The posttreatment ABR results were compared with the pretreatment values. A significant difference was found in group 1 (p:0,002), group 2 (p: 0,040), and group 4 (p: 0,027). When the posttreatment tests were compared with each other, there was a significant difference between groups 1 and 2 (p < 0,001), groups 1 and 3 (p < 0,001), and groups 1 and 5 (p < 0,001). CONCLUSIONS: The administration of 0.1 ml/kg and 3 ml/kg dose of NSO does not prevent ototoxicity. The 0.3 ml/kg dose of NSO effectively prevents GM-induced ototoxicity within both prophylactic and therapeutic use.

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC's mechano-electrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin-Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides and provide a series of hit compounds that will inform the design of future otoprotectants.

Investigation of Astaxanthin Effect on Cisplatin Ototoxicity in Rats by Using Otoacoustic Emission, Total Antioxidant Capacity, and Histopathological Methods.

BACKGROUND: Cisplatin-induced ototoxicity is related to oxidative stress. Astaxanthin is one of the most powerful antioxidants in nature. AIMS/OBJECTIVES: To investigate the protective effect of astaxanthin on cisplatin-induced ototoxicity. MATERIALS AND METHODS: Thirty-five Sprague Dawley female rats were divided into 5 groups: control, cisplatin, and cisplatin with 10, 20, and 40 mg/kg astaxanthin groups. Cisplatin group received a single intraperitoneal injection of 14 mg/kg cisplatin. While saline was administered in the control group, in the other 3 groups, 10, 20, and 40 mg/kg daily doses of astaxanthin were administered through orogastric cannula before administration of cisplatin. Baseline and 10th day otoacoustic emission tests were administered. An intracardiac blood sample was taken to measure total antioxidant capacity (TAC), and the cochleas of the animals were investigated histopathologically. RESULTS: Hearing level of astaxanthin 40 mg/kg + cisplatin group was higher at 24 kHz and 32 kHz frequencies compared to the cisplatin group. The TAC value of the cisplatin group was lower than both the control and astaxanthin + cisplatin groups (P < .05). On histopathological examination, the other groups were deformed compared to the control group, but no statistically significant difference was observed between the astaxanthin + cisplatin and cisplatin groups. CONCLUSIONS AND SIGNIFICANCE: Astaxanthin showed protective effect at high frequencies when it was administered at high dose. Thus, astaxanthin may have protective effect against cisplatin-induced ototoxicity.