title: Topographic and quantitative evaluation of gentamicin-induced damage to peripheral innervation of mouse cochleae.
abstract: Ototoxicity induced by aminoglycoside antibiotics appears to occur both in hair cells (HCs) and the cochlear nerves that innervate them. Although HC loss can be easily quantified, neuronal lesions are difficult to quantify because two types of afferent dendrites and two types of efferent axons are tangled beneath the hair cells. In the present study, ototoxicity was induced by gentamicin in combination with the diuretic agent furosemide. Neuronal lesions were quantified in cochlear whole-mount preparations combined with microsections across the habenular perforate (HP) openings to achieve a clear picture of the topographic relationship between neuronal damage and HC loss. Multiple immunostaining methods were employed to differentiate the two types of afferent dendrites and two types of efferent axons. The results show that co-administration of gentamicin and furosemide resulted in a typical dynamic pattern of HC loss that spread from the basal turn to the outer hair cells to the apex and inner hair cells, depending on the dose and survival time after drug administration. Lesions of the innervation appeared to occur at two stages. At the early stage (2-4 days), the loss of labeling of the two types of afferent dendrites was more obvious than the loss of labeled efferent axons. At the late stage (2-4 weeks), the loss of labeled efferent axons was more rapid. In the high-dose gentamicin group, the loss of outer HCs was congruent with afferent dendrite loss at the early stage and efferent axon loss at the late stage. In the low-dose gentamicin group, the loss of labeling for cochlear innervation was more severe and widespread. Thus, we hypothesize that the gentamicin-induced damage to cochlear innervation occurs independently of hair cell loss.
authors.affiliation: Department of Otolaryngology of the Affiliated Sixth People's Hospital and Otolaryngology Institute, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, PR China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Gerontology and Geriatrics, Affiliated Huadong Hospital, Shanghai Medical College, Fudan University, 221 West Yan An Road, Shanghai 200040, PR China. Electronic address: qingweir@aliyun.com.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Ruan
authors.affiliation: Otolaryngology Department, Shanghai 3rd People's Hospital, Medical School, Shanghai Jiaotong University, 280 Mo He Road, Shanghai 201900, PR China.
authors.forename: Huafei
authors.initials: H
authors.lastname: Ao
authors.affiliation: Department of Otolaryngology of the Affiliated Sixth People's Hospital and Otolaryngology Institute, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, PR China.
authors.forename: Jingchun
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Otolaryngology of the Affiliated Sixth People's Hospital and Otolaryngology Institute, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, PR China.
authors.forename: Zhengnong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Gerontology and Geriatrics, Affiliated Huadong Hospital, Shanghai Medical College, Fudan University, 221 West Yan An Road, Shanghai 200040, PR China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Gerontology and Geriatrics, Affiliated Huadong Hospital, Shanghai Medical College, Fudan University, 221 West Yan An Road, Shanghai 200040, PR China.
authors.forename: Ruxin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology of the Affiliated Sixth People's Hospital and Otolaryngology Institute, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, PR China; School of Human Communication Disorders, Dalhousie University, Halifax, Canada B3H1R2. Electronic address: jian.wang@dal.ca.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology of the Affiliated Sixth People's Hospital and Otolaryngology Institute, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, PR China. Electronic address: yinshankai@china.com.
authors.forename: Shankai
authors.initials: S
authors.lastname: Yin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000294:innervation / Q000473:pathology; D005260:Female; D005839:Gentamicins / Q000633:toxicity*; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways; D009847:Olivary Nucleus / Q000187:drug effects* / Q000473:pathology; D013136:Spiral Ganglion / Q000187:drug effects / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins
keywords: 4′,6-diamidino-2-phenylindole; A; Afferent dendrites; B; DAPI; Efferent axons; HC; HP; Hair cells; IHC; LOC; M; MOC; Mouse; OHC; OSL; SGNs; Spiral ganglion neurons; TMRD; Tetramethyl rhodamine dextran; apex segment; basal segment; habenular perforate; hair cell; inner hair cell; lateral olivary complex; medial olivary complex; middle segment; osseous spiral lamina; outer hair cell; spiral ganglion neurons; tetramethylrhodamine-conjugated dextran