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This review introduces the pathology of aminoglycoside antibiotic and the cisplatin chemotherapy classes of drugs, discusses oxidative stress in the inner ear as a primary trigger for cell damage, and delineates the ensuing cell death pathways. Among potentially ototoxic (damaging the inner ear) therapeutics, the platinum-based anti-cancer drugs and the aminoglycoside antibiotics are of critical clinical importance. Both drugs cause sensorineural hearing loss in patients, a side effect that can be reproduced in experimental animals. Hearing loss is reflected primarily in damage to outer hair cells, beginning in the basal turn of the cochlea. In addition, aminoglycosides might affect the vestibular system while cisplatin seems to have a much lower likelihood to do so. Finally, based on an understanding the mechanisms of ototoxicity pharmaceutical ways of protection of the cochlea are presented

Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiological actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochemical characteristics and signaling cascade associated with each receptor and provide insight into how these receptors are regulated in response to agonists. A key property of some of these receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as nuclear factor (NF)-κB, to regulate the expression of ARs. Recent observations of oligomerization of these receptors into homo- and heterodimers will be discussed. In addition, the importance of these receptors in the regulation of normal and pathological processes such as sleep, the development of cancers and in protection against hearing loss will be examined.

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This paper reviews intriguing recent findings on the mechanisms of drug induced hearing loss caused by two major classes of therapeutic agents: the aminoglycoside antibiotics and cisplatin. Both drug categories are nephrotoxic as well as ototoxic. Aminoglycosides and cisplatin target the outer hair cells in the basal turn of the cochlea to cause high frequency sensorineural hearing loss in a substantial percentage of patients treated with these drugs. Each group of agents appears to generate reactive oxygen species within the cochlea that trigger downstream mechanisms leading to cell death. Various protective agents including antioxidants show promise in protecting the inner ear from damage in experimental animals. The only successful double-blind, placebo controlled clinical trial using a protective agent to prevent ototoxicity was carried out in China. Aspirin or placebo was given in combination with gentamicin. A significant decrease in hearing loss was observed. Successful clinical implementation of protective agents will require a cautious approach, so that the therapeutic effect of the anti-infective agent or anti-neoplastic drug is not attenuated. This may require novel methods of administration of protective agents, such as injection within the middle ear. This would provide a maximal dose of protective agent without systemic interference with the desired effect of the ototoxic agent.

The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrificed and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45 +/- 0.012 nmol/mg] after cisplatin administration compared to 0.95-012 nmol/mg in control cochleae (P < 0.05). Superoxide dismutase, catalase activities and malondialdehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of significant hearing loss during the early days of use of cisplatin as a chemotherapeutic agent in cancer patients has stimulated research into the causes and treatment of this side effect. It has generally been accepted that hearing loss is produced by excessive generation of reactive oxygen species (ROS) in cell of the cochlea, which led to the development of various antioxidants as otoprotective agents. Later studies show that ROS could stimulate cochlear inflammation, suggesting the use of anti-inflammatory agents for treatment of hearing loss. In this respect, G-protein coupled receptors, such as adenosine A1 receptor and cannabinoid 2 receptors, have shown efficacy in the treatment of hearing loss in experimental animals by increasing ROS scavenging, suppressing ROS generation, or by decreasing inflammation. Inflammation could be triggered by activation of transient receptor potential vanilloid 1 (TRPV1) channels in the cochlea and possibly other TRP channels. Targeting TRPV1 for knockdown has also been shown to be a useful strategy for ensuring otoprotection. Cisplatin entry into cochlear hair cells is mediated by various transporters, inhibitors of which have been shown to be effective for treating hearing loss. Finally, cisplatin-induced DNA damage and activation of the apoptotic process could be targeted for cisplatin-induced hearing loss. This review focuses on recent development in our understanding of the mechanisms underlying cisplatin-induced hearing loss and provides examples of how drug therapies have been formulated based on these mechanisms.

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