Antioxidant protection in a new animal model of cisplatin-induced ototoxicity.
ABSTRACT Mortality is a major complication in animal models of cisplatin-induced hearing loss due to the systemic toxicity of the drug. Here we report on a novel two-cycle treatment in rats, each cycle consisting of four days of cisplatin injections (1 mg/kg, i.p., twice daily) separated by 10 days of rest. This regimen, similar to clinical courses of cancer chemotherapy, produced significant hearing loss without mortality. Auditory brain stem evoked responses were unchanged after the first cycle but were elevated by 40-50 dB at 16 and 20 kHz after the second. Loss of outer hair cells occurred after the second cycle, predominantly in the base of the cochlea. Total cochlear antioxidants declined progressively during drug treatment and were reduced to 60% of control values after the second cisplatin cycle. Co-administration of salicylate (100 mg/kg, s.c., twice daily) during both cycles or during the second cycle restored antioxidant levels and reduced cisplatin-induced threshold shifts. This model of cisplatin ototoxicity without mortality eliminates potentially confounding factors that may determine the survival of a special cohort of animals. The results also support the notion that reactive oxygen species are involved in cisplatin ototoxicity and show the potential usefulness of antioxidant treatment.
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ABSTRACT: Although auditory disorders are complex conditions, device-related modalities dominate current treatment. However, dysfunction from the central cortex to the inner ear apparatus is increasingly thought to be related to biochemical pathway abnormalities and to free radical-induced oxidative damage and chronic inflammation. Therefore, considering appropriate biologic therapy as an adjunct to standard care against these damaging factors may provide rational expansion of treatment options for otolaryngologists and audiologists. This review outlines the biologic concepts related to some auditory and vestibular conditions and details the current rationale for utilizing antioxidants for a spectrum of hearing disorders. The strategy is based on the authors' collective experience in antioxidant science and supported with published research, pilot animal data and preliminary clinical observations. A comprehensive micronutrient approach was developed to exploit these pathways, and demonstrated safety and efficacy against oxidative damage and inflammation and clinically relevant neuroprotection. Cooperative research with Department of Defense institutions used prospective, randomized designs to show (1) reduction in oxidative damage measured in plasma and urine over six months, (2) protection against oxidative damage during 12 weeks of intense military training, (3) protection against inflammation after total body blast exposure (rodents), (4) strong neuroprotection against chemically-induced Parkinson's disease (rodents), (5) nerve VIII function improvement after concussive head injury in military personnel, and (6) tinnitus improvement in majority of patients after 90-day evaluation. This systematic review of biologic strategies against hearing disorders combined with new animal and human observations may provide a rational basis for expanding current practice paradigms.American journal of otolaryngology 11/2009; 32(1):55-61. · 0.77 Impact Factor
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ABSTRACT: This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the molecular and biochemical pathways responsible for the regulation of the survival of hair cells and spiral ganglion neurons in the auditory portion of the inner ear. The pivotal role of ROS/RNS in ototoxicity makes them potentially valuable candidates for effective otoprotective strategies. In this review, we describe the major characteristics of ROS/RNS and the different oxidative processes observed during ototoxic cascades. At each step, we discuss their potential as therapeutic targets because an increasing number of compounds that modulate ROS/RNS processing or targets are being identified.Current Medicinal Chemistry 01/2010; 17(30):3591-604. · 4.86 Impact Factor