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      Cisplatin effects on guinea pigs: cochlear histology and genotoxicity

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          Abstract

          Abstract

          To understand how the DNA answers to external agents such as cisplatin may be relevant to the diagnosis and treatment of hearing disorders caused by the administration of such drug.

          Objectives

          To investigate the cisplatin influence on the cochlea and DNA of guinea pigs.

          Material and Methods

          Experimental study carried out with 12 guinea pigs (Cavia porcellus). The inclusion criterion was the presence of Preyer's reflex and distortion-product otoacoustic emissions. Guinea pigs were divided into two groups: Control Group (CG) - made up of six guinea pigs, to which we administrated saline solution during six consecutive days, intraperitoneally; and a Study Group (SG) - made up of six guinea pigs, to which we administrated cisplatin during six consecutive doses of 3mg/kg/day intraperitoneally. Twenty-four hours after the last administration of cisplatin the guinea pigs were slaughtered, blood samples were collected and the cochleae were removed.

          Results

          The administration of cisplatin did not cause identifiable changes to the DNA. Histological analysis showed changes in the organ of Corti and spiral ganglion.

          Conclusion

          Cisplatin causes changes in cochlear histology, such as the loss of the normal microcytoarchitecture of the organ of Corti, and reduction of neurons of the spiral ganglion with cell alterations, however, DNA damage was not detected.

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          Most cited references46

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          Free radicals in the physiological control of cell function.

          At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
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            Mechanisms of cisplatin-induced ototoxicity and prevention.

            Cisplatin is a widely used chemotherapeutic agent to treat malignant disease. Unfortunately, ototoxicity occurs in a large percentage of patients treated with higher dose regimens. In animal studies and in human temporal bone investigations, several areas of the cochlea are damaged, including outer hair cells in the basal turn, spiral ganglion cells and the stria vascularis, resulting in hearing impairment. The mechanisms appear to involve the production of reactive oxygen species (ROS), which can trigger cell death. Approaches to chemoprevention include the administration of antioxidants to protect against ROS at an early stage in the ototoxic pathways and the application of agents that act further downstream in the cell death cascade to prevent apoptosis and hearing loss. This review summarizes recent data that shed new light on the mechanisms of cisplatin ototoxicity and its prevention.
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              The cochlear targets of cisplatin: an electrophysiological and morphological time-sequence study.

              Cisplatin ototoxicity has at least three major targets in the cochlea: the stria vascularis, the organ of Corti, and the spiral ganglion. This study aims to differentiate between these three targets. In particular, we address the question of whether the effects at the level of the organ of Corti and spiral ganglion are mutually dependent or whether they develop in parallel. This question was approached by studying the ototoxic effects while they develop electrophysiologically and comparing these to earlier presented histological data [Van Ruijven et al., 2004. Hear. Res. 197, 44-54]. Guinea pigs were treated with intraperitoneal injections of cisplatin at a dose of 2 mg/kg/day for either 4, 6, or 8 consecutive days. This time sequence has not revealed any evidence of one ototoxic process triggering another. Therefore, we have to stay with the conclusion of Van Ruijven et al. (2004) that both processes run in parallel.
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                Author and article information

                Journal
                Braz J Otorhinolaryngol
                Braz J Otorhinolaryngol
                Brazilian Journal of Otorhinolaryngology
                Elsevier
                1808-8694
                1808-8686
                19 October 2015
                Nov-Dec 2011
                19 October 2015
                : 77
                : 6
                : 728-735
                Affiliations
                [1 ]MSc in Human Communication Disorders - UFSM, Speech and Hearing Therapy
                [2 ]PhD; Associate Professor of the Federal University of Santa Maria (UFSM) at the Speech and Hearing Therapy Program and Graduate Program in Human Communication Disorders
                [3 ]PhD; Full Professor at the Department of Morphology of the Federal University of Santa Maria (UFSM) and Graduate Program in Human Communication Disorders
                [4 ]Biomedic; MSc Student at the Graduate Program in Toxicological Biochemistry -UFSM
                [5 ]Pharmacist. MSc Student of the Graduate Program in Toxicological Biochemistry - UFSM. Federal University of Santa Maria
                Author notes
                [* ]Send correspondence to: Cacineli Marion de Franceschi - Rua Caetano José Rigon, N o 466, Bairro Vera Cruz. Sobradinho - RS. CEP: 96900-000. CAPES
                Article
                S1808-8694(15)30729-1
                10.1590/S1808-86942011000600009
                9443774
                22183279
                e089fb78-d1db-4fe7-ba8c-c3f2ab71f08d
                .

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Categories
                Original Article

                hair cells,auditory,genotoxicity,guinea pigs,histology
                hair cells, auditory, genotoxicity, guinea pigs, histology

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