Ototoxicity: Mechanisms of Cochlear Impairment and its Prevention

Abstract

Aminoglycosides, cisplatin, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used pharmacological agents. There is a possibility, however, that the use of these agents may induce transient or permanent hearing loss and tinnitus as side effects. Recent animal studies have clarified mechanisms leading to the ototoxicity induced by these agents, at least in part. The permanent hearing loss caused by aminoglycosides and cisplatin is suggested to be predominantly associated with the apoptotic death of outer hair cells. Both drugs generate reactive oxygen species (ROS) in the inner ear. ROS can activate cell-death pathways such as the c-Jun Nterminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, which in turn, induce hair cell apoptosis. On the other hand, the abuse of NSAIDs may transiently cause tinnitus and mild to moderate hearing loss. NSAIDs impair the active process of the outer hair cells and affect peripheral and central auditory neurons. Conversely, recent reports clarified that NSAIDs are potential therapeutic agents against cochlear injuries. In this review, recent findings from animal studies regarding the ototoxicity induced by aminoglycosides, cisplatin, and NSAIDs are summarized. Their ototoxic mechanisms are focused on.

Cobalt-Induced Ototoxicity in Rat Postnatal Cochlear Organotypic Cultures

“…As with many other ototoxic drugs, CoCl 2 was significantly more toxic to OHC than IHC at intermediate doses and durations (Fig. 2h), consistent with the preferential ototoxic effects of aminoglycosides (Taylor et al 2008), cisplatin, and other toxic compounds (Tabuchi et al 2011). We are aware of only one histopathologic study of Co ototoxicity in rabbits which reported on the gross qualitative degenerative changes in the hair cells and SGN (Apostoli et al 2013) following a single intravenous dose of Co.…”

Neurotrophic and antioxidant effects of silymarin comparable to 4-methylcatechol in protection against gentamicin-induced ototoxicity in guinea pigs

“…Under such condition, ROS attacks most of cellular components with subsequent formation of lipid peroxides and disruption of enzymes activity, ion channels, and receptors [59]. ROS has been postulated to induce hair cell apoptosis via activation of cell-death pathways such as the c-Jun N terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) [60]. In this context, the present results showed that gentamicin-induced ototoxicity is associated with a status of oxidative stress indicated as marked decrease in catalase activity and increase in MDA as a representative marker of lipid peroxidation.…”

Radiation-induced Cochlea Hair Cell Death: Mechanisms and Protection

“…Although the relationship between ROS and apoptosis has not yet been clearly brought to light, ROS is believed to play a key role in the promotion of apoptosis by affecting mitochondrial permeability, release of cytochrome c and activation of p53, caspases, JNK and p38 mitogen activated protein kinases (MAPK) pathways in auditory cells (Devarajan et al, 2002;Tabuchi et al, 2011). A recent study demonstrated low concentrations of H 2 O 2 mortally injured the hair cells by reducing mitochondrial membrane potential and mitochondrial produced antioxidants (Baker and Staecker, 2012).…”

“…Caspase-9 (as an upstream caspase) and caspase-3 (as a downstream caspase) have been shown to be key mediators of cochlea hair cell death induced by drugs and noise (Cheng et al, 2005). The interactions between them and other species such as ROS, p53 and cytochrome c from the mitochondria in hair cells have been reported in several studies (Devarajan et al, 2002;Cheng et al, 2005;Tabuchi et al, 2011). But studies on their roles in radiated hair cells are very limited.…”