8-hydroxy-2--deoxyguanosine and Hearing-Loss

Cisplatin is employed for chemotherapeutic purposes in several types of adult and pediatric cancer. However, side-effects including nephrotoxicity, ototoxicity, gastrointestinal effects and neuropathy restrict the use of the drug due to their adverse impacts on quality of life. This study aimed to determine whether levosimendan exhibits a protective effect against cisplatin-related ototoxicity in a rat model by means of functional, biochemical and histochemical analysis.. The study was employed with 24 female Sprague Dawley rats. After distortion product otoacoustic emissions (DPOAE) tests applied to all rats, rats were randomly assigned into four groups of six animals each. A single intraperitoneal 15 mg/kg dose of cisplatin was administered to Cisplatin group. Levosimendan group received intraperitoneal levosimendan at a dose of 100 mg/kg for five consecutive days. Cisplatin + Levosimendan group received intraperitoneal levosimendan at a dose of 100 mg/kg for five consecutive days and a single intraperitoneal dose of 15 mg/kg cisplatin at 3rd day of the study. Control group received 8 mL/kg/day intraperitoneal saline solution for five consecutive days. The DPOAE test was repeated on the 6th day of the study. All rats were then sacrificed, the cochleas were removed and set aside for biochemical and histopathological analyses.. A significant increase in levels of Malondialdehyde (MDA) and significantly lower activities of superoxide dismutase (SOD) and Glutathione peroxidase (GPx) were observed at rats of cisplatin group. Administration of levosimendan showed significantly lower cochlear MDA levels, while SOD and GPx activities both increased significantly. The DPOAE test performed at 6th day of the study showed a significant impairment in the signal-noise ratio (SNR) levels of rats in Cisplatin group. The SNR levels of rats treated with levosimendan were significantly higher than those of cisplatin group and were similar to those of the control group. Cisplatin impaired the cochlear structure and a severe Caspase 3 and 8-hydroxy-2' -deoxyguanosine (8-OHdG) immunopositivity was observed at cochlea of the rats of cisplatin group. Administration of levosimendan protected the structure of cochlea and there was a mild Caspase 3 and 8OHdG immunopositivity.. Our data demonstrate that levosimendan protects hearing against cisplatin-induced ototoxicity and obviates cellular degeneration. It also significantly reduces oxidative stress and apoptosis, probable mechanisms involved in ototoxicity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cisplatin; Cochlea; Deoxyguanosine; Disease Models, Animal; Female; Glutathione Peroxidase; Hearing; Hearing Loss; Malondialdehyde; Otoacoustic Emissions, Spontaneous; Oxidative Stress; Phosphodiesterase 3 Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; Signal-To-Noise Ratio; Simendan; Superoxide Dismutase

Inner ear barotrauma (IEB) that is caused by acute pressure changes can often lead to permanent severe sensorineural hearing loss (SNHL). However, the mechanism that causes IEB is still unknown. In the current study, we assessed the involvement of reactive oxygen species (ROS) in IEB and the therapeutic effect of 3-methyl 1-phenyl-2-pyrazolin-5-one (edaravone), which is a free radical scavenger. To create the IEB model, guinea pigs were subjected to quick pressure changes that resulted in acute SNHL. The animals were then divided into two groups, an edaravone-treated IEB group and a non-treated IEB group that only received normal saline. Immunohistochemical analyses for 8-hydroxy-2-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) were performed to examine the amount of oxidative DNA damage and lipid peroxidation that occurred in guinea pig cochlea. To assess the curative efficacy of edaravone, auditory brainstem response (ABR) testing was performed to evaluate auditory function. Strong immunoreactivities against 8-OHdG and 4-HNE were observed in the inner ear tissues of the non-treated IEB group. Lesser amounts of immunoreactivity were observed in the same region of the edaravone-treated IEB group as compared to the non-treated IEB group. Furthermore, ABR measurement revealed that there was a faster improvement in the threshold shift for the edaravone-treated IEB group as compared to that of the non-treated IEB group. At the final 7-week time point, the threshold shift for the edaravone-treated IEB group was significantly smaller as compared to the non-treated IEB group. These results strongly suggest that ROS is produced in the cochlea in response to acute pressure changes and that ROS plays an important role in the pathophysiology of IEB. Furthermore, edaravone treatment had a therapeutic effect on IEB-induced acute SNHL and thus, edaravone might possibly be able to be used as a therapeutic treatment for IEB.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antipyrine; Barotrauma; Cochlea; Deoxyguanosine; Ear, Inner; Edaravone; Evoked Potentials, Auditory, Brain Stem; Female; Free Radical Scavengers; Guinea Pigs; Hearing Loss; Immunohistochemistry; Organ of Corti; Pressure; Spiral Ganglion; Stria Vascularis