OTOTOXIC MODEL OF OXALIPLATIN AND PROTECTION FROM NICOTINAMIDE ADENINE DINUCLEOTIDE

作     者：DING Dalian JIANG Haiyan FU Yong LI Yongqi Richard Salvi Shinichi Someya Masaru Tanokura 

作者机构：Center for Hearing and DeafnessState University of New York at Buffalo Sixth People’s HospitalShanghai Oriental Otolaryngology InstituteShanghai Jiao Tong University Xiangya HospitalCentral South University Department of Applied Biological ChemistryUniversity of Tokyo The First Officiated HospitalCollege of MedicineZhejiang University The Third Affiliated Hospital of Sun Yat-Sen University University of Florida 

出 版 物：《Journal of Otology》 (中华耳科学杂志（英文版）)

年 卷 期：2013年第8卷第1期

页      面：63-71页

学科分类：1003[医学-口腔医学] 1002[医学-临床医学] 100213[医学-耳鼻咽喉科学] 10[医学] 

主　　题：oxaliplatin apoptosis copper transporter nicotinamide adenine dinucleotide 

摘      要：Oxaliplatin, an anticancer drug commonly used to treat colorectal cancer and other tumors, has a number of serious side effects, most notably neuropathy and ototoxicity. To gain insights into its ototoxic profile, oxaliplatin was applied to rat cochlear organ cultures. Consistent with it neurotoxic propensity, oxaliplatin selectively damaged nerve fibers at a very low dose 1 μM. In contrast, the dose required to damage hair cells and spiral ganglion neurons was 50 fold higher (50 μM). Oxailiplatin-induced cochlear lesions initial-ly increased with dose, but unexpectedly decreased at very high doses. This non-linear dose response could be related to depressed oxaliplatin uptake via active transport mechanisms. Previous studies have demon-strated that axonal degeneration involves biologically active processes which can be greatly attenuated by nicotinamide adenine dinucleotide (NAD+). To determine if NAD+would protect spiral ganglion axons and the hair cells from oxaliplatin damage, cochlear cultures were treated with oxaliplatin alone at doses of 10 μM or 50 μM respectively as controls or combined with 20 mM NAD+. Treatment with 10 μM oxaliplatin for 48 hours resulted in minor damage to auditory nerve fibers, but spared cochlear hair cells. However, when cochlear cultures were treated with 10 μM oxaliplatin plus 20 mM NAD+, most auditory nerve fibers were intact. 50 μM oxaliplatin destroyed most of spiral ganglion neurons and cochlear hair cells with apop-totic characteristics of cell fragmentations. However, 50 μM oxaliplatin plus 20 mM NAD+treatment great-ly reduced neuronal degenerations and hair cell missing. The results suggested that NAD+provides signifi-cant protection against oxaliplatin-induced neurotoxicity and ototoxicity, which may be due to its actions of antioxidant, antiapoptosis, and energy supply.