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Trimethyltin-induced cochlear degeneration in rat

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Journal of Otology 2016年第3期11卷 118-126页

作者： Jintao Yu Dalian Ding Hong Sun Richard Salvi Jerome A.Roth Department of Otolaryngology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Center for Hearing and Deafness University at Buffalo Department of Otolaryngology Head and Neck Surgery Xiangya HospitalCentral South University Department of Pharmacology and Toxicology University at Buffalo

Trimethyltin(TMT) is an occupational and environmental health hazard behaving as a potent neurotoxin known to affect the central nervous system as well as the peripheral auditory ***,the mechanisms underlying TMT-induced ototoxicity are poorly *** elucidate the effects of TMT on the cochlea,a single injection of 4 or 8 mg/kg TMT was administered intraperitoneally to adult *** compound action potential(CAP) threshold was used to assess the functional status of the cochlea and histological techniques were used to assess the condition of the hair cells and auditory nerve *** at 4 mg/kg produced a temporary CAP threshold elevation of 25-60 dB that recovered by 28 d *** there was no hair cell loss with the 4 mg/kg dose,there was a noticeable loss of auditory nerve fibers particularly beneath the inner hair *** at 8 mg/kg produced a large permanent CAP threshold shift that was greatest at the high *** CAP threshold shift was associated with the loss of outer hair cells and inner hair cells in the basal,high-frequency region of the cochlea,considerable loss of auditory nerve fibers and a significant loss of spiral ganglion neurons in the basal *** ganglion neurons showed evidence of soma shrinkage and nuclear condensation and fragmentation,morphological features of apoptotic cell ***-induced damage was greatest in the high-frequency,basal region of the cochlea and the nerve fibers beneath the inner hair cells were the most vulnerable structures.

关键词： Trimethyltin ototoxicity Hair cells Nerve fibers Spiral ganglion neurons

Anatomy and physiology of peripheral auditory system and commen causes of hearing loss

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Journal of Otology 2009年第1期4卷 -页

作者： ZHANG Qing1,DUAN Mao-li1-4 1 Department of Otorhinolarygology,The 2nd Affiliated Hospital of Xi’an Jiaotong University,School of Medicine,Xi’an Jiaotong University,Xi’an,P.R.China 2 Department of clinical neuroscience,3,Department of Otolaryngology,Karolinska Hospital,171 76 Stockholm,Sweden 4 Department of Otolaryngology,Affiliated Hospital of Anhui Medical University,China Department of Otorhinolarygology The 2nd Affiliated Hospital of Xi’ an Jiaotong UniversitySchool of Medicine Xi’ an Jiaotong University Xi’ an P.R.China Department of clinical neuroscience Karolinska Hospital 171 76 Stockholm Sweden Department of Otolaryngology Karolinska Hospital 171 76 Stockholm Sweden Department of Otolaryngology Affiliated Hospital of Anhui Medical University China

For Otolaryngologist,it is the most important to know the principle of anatomy,physiology and common *** but more concise summary has been sum up in the following review in order to help young ENT doctor to understand... 详细信息

关键词： inner hair cell outer hair cell spiral ganglion neuron ototoxicity

Ototoxic effects of mefloquine in cochlear organotypic cultures

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Journal of Otology 2009年第2期4卷 76-85页

作者： Richard Salvi Center for Hearing and Deafness State University of New York at Buffalo

Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate the ototoxic and neurotoxic potential of mefloquine, we treated cochlear organotypic cultures and spiral ganglion cultures with various concentrations of mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01 mM. Hair cell loss progressed from base to apex and from outer to inner hair cells with increasing dose. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. To investigate the mechanisms underlying mefloquine-induced cell death, cochlear cultures were stained with TO-Pro-3 to identify morphological changes in the nucleus, and with carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3 to determine caspase-mediated cell death. TO-Pro-3-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine treatment. These three caspases were also expressed in support cells, although labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat cochlea by initially activating cell death signaling pathways on the cell membrane and in mitochondria.

关键词： Mefloquine ototoxicity neuropathology outer hair cell inner hair cell spiral ganglion neurons axon degeneration

Modulation of copper transporters in protection against cisplatin-induced cochlear hair cell damage

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Journal of Otology 2011年第2期6卷 51-59页

作者： Richard Salvi Center for Hearing and Deafness Department of Communicative Disorders and SciencesState University of New York at Buffalo137 Cary Hall3435 Main StreetBuffaloNY 14214 USA

Cisplatin belongs to platinum-based drugs and is widely used in cancer *** is one of the major dose limiting side-effects of *** toxicity to occur cisplatin must first be transported from the bloodstream into cochlear *** copper transporters are considered pathways for regulating the uptake and translocation of cisplatin into cells:Ctr1,ATP7A and *** recent study with cochlear organotypic cultures shows that cochlear hair cells can be destroyed by cisplatin at low concentrations from 10μm to 100μ***,high doses of cisplatin cannot damage hair cells,maybe due to intrinsic feedback reactions that increase export of platinum by ATP7B when the platinum concentration is high in extracellular *** is a specific copper transporter inhibitor that can block the entrance of copper and platinum,and may prevent cisplatin-induced cochlear hair cell *** evaluate this hypothesis,we treated cochlear organotypic cultures with cisplatin (10 μm or 50 μm) alone,or cisplatin combined with cimitidine at concentrations ranging from 10-2000 μm for 48 *** at 10 μm damaged about 20% hair *** contrast,when cimitidine (10 μm,100 μm and 2000 μm) was added to the culture,near 100% cochlear hair cell *** higher concentration (50 μm),cisplatin destroyed about 80% of cochlear hair ***,100 μmcimitidine rescued about 50% hair cells from cisplatin damage,and 2000μm cimitidine protected about 80% hair *** data of western blot showed that CTR1 and ATP7B expressions were increased in cisplatin treated cochlear tissue,but cimitidine significantly reduced CTR1 and *** addition,ATP7A expression was depressed a little after cisplatin *** that Ctr1 is involved in copper and platinum influx,but the ATP7A and ATP7B are copper export transporters,the results suggest that cimitidine can effectively block the entrance by copper transporters and stop the influx of cisplatin.

关键词： cisplatin copper transporter ototoxicity cochlear hair cell

Pattern of hair cell loss and delayed peripheral neuron degeneration in inner ear by a high-dose intratympanic gentamicin

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Journal of Otology 2014年第3期9卷 126-135页

作者： Jintao Yu Dalian Ding Fengjun Wang Haiyan Jiang Hong Sun Richard Salvi Department of Otolaryngology Head and Neck Surgery Xiangya HospitalCentral South University Center for Hearing and Deafness State University of New York at Buffalo

To gain insights into the ototoxic effects of aminoglycoside antibiotics(AmAn) and delayed peripheral ganglion neuron death in the inner *** animal models were widely used with several different approaches including AmAn systemic injections,combination treatment of AmAn and diuretics,or local application of *** these approaches,systemic AmAn treatment alone usually causes incomplete damage to hair cells in the inner ***-administration of diuretic and AmAn can completely destroy the cochlear hair cells,but it is impossible to damage the vestibular *** the approach of AmAn local application can selectively eliminate most sensory hair cells in the inner ***,AmAn local application is more suitable for studies for complete hair cell destructions in cochlear and vestibular system and the following delayed peripheral ganglion neuron *** current studies,guinea pigs were unilaterally treated with a high concentration of gentamicin(GM,40 nig/ml) through the tympanic membrane into the middle ear *** functions and vestibular functions were measured before and after GM *** loss of hair cells and delayed degeneration of ganglion neurons in both cochlear and vestibular system were quantified 30 days or 60 days after *** results showed that both auditory and vestibular functions were completely abolished after GM *** sensory hair cells were totally missing in the cochlea,and severely destroyed in vestibular *** delayed spiral ganglion neuron death 60 days after the deafening procedure was over 50%.However,no obvious pathological changes were observed in vestibular ganglion neurons 60 days *** results indicated that a high concentration of gentamycin delivered to the middle ear cavity can destroy most sensory hair cells in the inner ear that subsequently causes the delayed spiral ganglion neuron *** model might be useful for studies of hair cell regeneration

关键词： Cochlea Vestibular system Gentamicin Local medication ototoxicity

OTOTOXIC EFFECTS OF CARBOPLATIN IN ORGANOTYPIC CULTURES IN CHINCHILLAS AND RATS

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Journal of Otology 2012年第2期7卷 92-101页

作者： DING Dalian JIANG Haiyan FU Yong Richard SALVI Shinichi SOMEYA Masaru TANOKURA Center for Hearing and Deafness State University of New York at Buffalo Graduate School of Agricultural and Life Sciences University of Tokyo Departments of Aging and Geriatric Research Division of Biology of Aging University of Florida

Carboplatin, a second-generation platinum chemotherapeutic drug, is considerably less ototoxic than cisplatin. While common laboratory species such as mice, guinea pigs and rats are highly resistant to carboplatin ototoxicity, the chinchilla stands out as highly susceptible. Moreover, carboplatin causes an unusual gradient of cell death in chinchillas. Moderate doses selectively damage type I spiral ganglion neurons (SGN) and inner hair cells (IHC) and the lesion tends to be relatively uniform along the length of the cochlea. Higher doses eventually damage outer hair cells (OHC), but the lesion follows the traditional gradient in which damage is more severe in the base than the apex. While carboplatin ototoxicity has been well documented in adult animals in vivo, little is known about its in vitro toxicity. To elucidate the ototoxic effects of carboplatin in vitro, we prepared cochlear and vestibular organotypic cultures from postnatal day 3 rats and adult chinchillas. Chinchilla cochlear and vestibular cultures were treated with carboplatin concentrations ranging from 50 μM to 10 mM for 48 h. Consistent with in vivo data, carboplatin selectively damaged IHC at low concentrations (50-100 μM). Surprisingly, IHC loss decreased at higher doses and IHC were intact at doses exceeding 500 μM. The mechanisms underlying this nonlinear response are unclear but could be related to a decrease in carboplatin uptake via active transport mechanisms (e.g., copper). Unlike the cochlea, the carboplatin dose-response function increased with dose with the highest dose destroying all chinchilla vestibular hair cells. Cochlear hair cells and auditory nerve fibers in rat cochlear organotypic cultures were unaffected by carboplatin concentrations <10 μM; however, the damage in OHC were more severe than IHC once the dose reached 100 μM. A dose at 500 μM destroyed all the cochlear hair cells, but hair cell loss decreased at high concentrations and nearly all the cochlear hair cells were pre

关键词： Carboplatin ototoxicity organotypic culture

Detection of apoptosis by RT-PCR array in mefloquine-induced cochlear damage

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Journal of Otology 2011年第1期6卷 1-9页

作者： DING Da-lian Someya Shinichi JIANG Hai-yan QI Wei-dong YU Dong-zhen Center for Hearing and Deafness State University of New York at Buffalo Departments of Aging and Geriatric Research Division of Biology of Aging University of Florida Department of Otolaryngology Head and Neck Surgery Huashan Hospital Affiliated Fudan University Department of Otolaryngology Head and Neck Surgery Six People＇s Hospital of Shanghai Jiao Tong University Graduate School of Agricultural and Life Sciences University of Tokyo Department of Otolaryngology Head and Neck Surgery Xiangya Hospital of Central South University

Objective To investigate the occurrence and possible mechanisms of apoptosis in cochlear epithelium and spiral ganglion neurons after mefloquine treatment. Methods We used quantitative RT-PCR apoptosis-focused gene arrays （96-well, 84 apoptosis related genes） to assess changes of gene expression in the cochlear basilar membrane （hair cells-supporting cells） and spiral ganglion neurons of rat cochlear organotypic cultures treated with 100 IxM mefloquine for 3 h. Results Significant up-or down-regulation in gene expression was detected in 23 genes in the cochlear basilar membrane, and in 32 genes in the spiral ganglion neurons compared with time-matched controls. The responding genes could be classified as pro-or anti-apoptotic, and were mainly implicated in the Bcl-2, Caspase, Card, IAP, TNF ligand / TNF receptor, Death domain / Death effector domain, DNA damage / p53, and NF-kappa B families. Synthetic analysis suggested that these families could be revised to two major pathways mainly involved in t]he death receptor-mediated signaling pathway and apoptotic mitochondrial pathway. In addition, it was found that numerous anti-apoptotic genes such as Bcl2al, Birclb, Birc3, Birc4, Bnipl, Cflar, II10, Lhx4, Mcll, Nfkbl, Prlr, Prok2, and TNF were greatly up-regulated in the cochlear tissue, which might imply the co-existence of protective response in the ceils at the early stage of mefloquine-induced damage.

关键词： mefloquine ototoxicity apoptosis cochlea spiral ganglion neurons hair cells gene expression

Gene transfection mediated by polyethyleneiminepolyethylene glycol nanocarrier prevents cisplatininduced spiral ganglion cell damage

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Neural Regeneration Research 2015年第3期10卷 425-431页

作者： Guan-gui Chen Min Mao Li-zi Qiu Qi-ming Liu Department of Otorhinolaryngology the Second Affiliated Hospital of Guangzhou Medical University

Polyethyleneimine-polyethylene glycol （PEI-PEG）, a novel nanocarrier, has been used for trans- fection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein （XIAP） in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Audito- ry brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.

关键词： nerve regeneration polyethyleneimine-polyethylene glycol spiral ganglion cells X-linkedinhibitor of apoptosis protein gene therapy nanocarrier cisplatin neural regeneration ototoxicity cochlea

Assessment of Hearing Status by Pure Tone Audiogram—An Institutional Study

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International Journal of Otolaryngology and Head & Neck Surgery 2015年第5期4卷 375-380页

作者： Ganesh Kumar Balasubramanian Ramanathan Thirunavukkarasu Ramesh Babu Kalyanasundaram Gitanjali Narendran Thanjavur Medical College Thanjavur India

Aim: To assess the hearing status of the study subjects in terms of degree and type of hearing loss, and establish the burden of this disability in the society. Materials and methods: This is a prospective study conducted in patients who attend our OPD. After an otorhinolaryngeal examination, all the patients were subjected to pure tone audiometry using MAICA-MA52 audiometer. Results: Our study comprises 1012 males (64%) and 563 females (36%). Out of this, about 15% have conductive deafness and 42% have sensorineural hearing loss. About 29% suffer from mild hearing loss, 26% moderate and 11% severe hearing loss. The alarming information is that about 5% have total hearing loss of Sudden Sensorineural type (SSNHL). Conclusion: Pure tone audiometry is cost effective and easy to perform. Early diagnosis and timely intervention will reduce the morbidity of deafness in our country. Hence it is necessary to identify and treat sudden sensorineural hearing loss and noise induced hearing loss at an early stage.

关键词： Pure Tone Audiogram Conductive Deafness Sudden Sensorineural Hearing Loss ototoxicity Presbyacusis Noise Induced Hearing Loss