Efficacy of three drugs for protecting against gentamicin‐induced hair cell and hearing losses

Abstract

BACKGROUND AND PURPOSE Exposure to an ototoxic level of an aminoglycoside can result in hearing loss. In this we study investigated the otoprotective efficacy of dexamethasone (DXM), melatonin (MLT) and tacrolimus (TCR) in gentamicin (GM)-treated animals and cultures. EXPERIMENTAL APPROACH Wistar rats were divided into controls (treated with saline); exposed to GM only (GM); and three GM-exposed groups treated with either DXM, MLT or TCR. Auditory function and cochlear surface preparations were studied. In vitro studies of oxidative stress, pro-inflammatory cytokine mRNA levels, the MAPK pathway and caspase-3 activation were performed in organ of Corti explants from 3-day-old rats. KEY RESULTS DXM, MLT and TCR decreased levels of reactive oxygen species in GM-exposed explants. The mRNA levels of TNF-α, IL-1β and TNF-receptor type 1 were significantly reduced in GM + DXM and GM + MLT groups. Phospho-p38 MAPK levels decreased in GM + MLT and GM + TCR groups, while JNK phosphorylation was reduced in GM + DXM and GM + MLT groups. Caspase-3 activation decreased in GM + DXM, GM + MLT and GM + TCR groups. These results were consistent with in vivo results. Local treatment of GM-exposed rat cochleae with either DXM, MLT or TCR preserved auditory function and prevented auditory hair cell loss. CONCLUSIONS AND IMPLICATIONS In organ of Corti explants, GM increased oxidative stress and initiated an inflammatory response that led to the activation of MAPKs and apoptosis of hair cells. The three compounds tested demonstrated otoprotective properties that could be beneficial in the treatment of ototoxicity-induced hearing loss.

Autophagy-related protein 12 associates with anti-apoptotic B cell lymphoma-2 to promote apoptosis in gentamicin-induced inner ear hair cell loss

“…This model has been used and characterized in numerous studies (35)(36)(37). The present study demonstrated the occurrence of autophagy in this model using multiple techniques, including examination of autophagosomes by electron microscopy, immunofluorescence and immunoblot analysis of LC3-II formation.…”

Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

“…Among the earliest observations of free radical formation in OHCs after aminoglycoside treatment was in vitro formation of hydrogen peroxide and hydroxyl radicals in OHCs treated with gentamicin or kanamycin ; superoxide and hydrogen peroxide radicals were later shown to decrease auditory function in vivo (Clerici and Yang 1996). Production of ROS after gentamicin has been confirmed in other in vitro models (Basappa et al 2010;Sha and Schacht 1999a;Bas et al 2012), and ROS formation in the inner ear has been shown in tissues harvested from mice treated in vivo with kanamycin (Jiang et al 2005). ROS production may be secondary to actions of gentamicin as an iron chelator, as it appears that the irongentamicin complex drives free radical formation (Priuska and Schacht 1995).…”

“…When the nitric oxide (NO) inhibitor nitro-L-arginine methyl ester (L-NAME) was delivered via repeat injections through the tympanic membrane, L-NAME reduced gentamicin-induced hearing loss in the high-frequency range, but gave no protection in the middle or low frequencies (Nordang and Anniko 2005). A surgical approach to the cochlea to allow either gelfoam to be placed on the round or a drug delivery cannula to be inserted through the wall of the cochlea may have allowed agents including dexamethasone, melatonin, and tacrolimus to provide greater protection, but ABR thresholds were assessed using clicks, making frequency specific conclusions more difficult (Bas et al 2012). Therapeutic interventions that require surgical intervention are unlikely to have widespread clinical utility and they will be difficult to adopt in developing countries, where aminoglycoside use is greatest.…”

“…It appears an endogenous antioxidant defense is initially mounted, and ultimately overwhelmed, as endogenous antioxidant stores are depleted after aminoglycoside therapy. Superoxide dismutase (SOD), catalase, GSH, and glutathione peroxidase (GPx) were all reduced in cochleas harvested from guinea pigs treated with amikacin (Klemens et al 2003) as well as tissue cultures treated with gentamicin (Bas et al 2012). Consistent with endogenous antioxidant defense, transgenic mice that overexpress SOD1 are more resistant to kanamycin-induced ototoxicity than wild-type mice (Sha et al 2001b).…”

Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

“…After exposure to brimonidine, there is phosphorylation of the extracellular signal-activated kinases 1/2 (Erk1/2) in injured retinal homogenates [Fujita et al, 2013] or as a physiological response to α 2 -AR activation in uninjured retinal homogenates [Lai et al, 2002] and chicken Müller cells [HarunOr-Rashid et al, 2014]. Phosphorylation of Erk1/2 has especially been shown to mediate HC survival [Bas et al, 2012;Kurioka et al, 2015], and one way to protect OHCs from gentamicin-induced toxicity is increased activation of MAPK/Erk [Battaglia et al, 2003].…”