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Ototoxic effects of mefloquine in cochlear organotypic cultures

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

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Spontaneous Proliferation in Organotypic Cultures of Mouse Cochleae

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Journal of Otology 2008年第2期3卷 76-83页

作者： richard salvi Center for Hearing and Deafness State University of New York at BuffaloNY USA

Cells in mammalian cochleae virtually stop proliferation and exit cellular circle before birth. Consequently, hair cells and spiral ganglion neurons destroyed by ototoxic factors cannot be replaced through proliferative regeneration. However, substantial proliferation occurs in organotypic cultures of cochleae from postnatal mice. In the present study, we studied the time course of proliferative growth in cultures of mouse cochlea explants obtained from up to 12 postnatal days. The mitotic nature of this growth was confirmed by bromodeoxyuridine (BrdU) staining and expression of proliferation cell nuclear antigen (PCNA) evaluated with real-time quantitative poly-merase chain reaction(RT-PCR). Similar growth time course was found in the cochlear explants of different postnatal ages. The new growth reached its maximum at around 2 days in culture followed by a slow-down, and virtually stopped after 5 days of culture. The possible mechanisms and the significance of this proliferation are discussed.

关键词： organotypic culture cochlea proliferation bromodeoxyuridine (BrdU) proliferation cell nuclear antigen(PCNA) real-time quantitative polymerase chain reaction(RT-PCR)

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Lead neurotoxicity in rat cochlear organotypic cultures

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Journal of Otology 2011年第2期6卷 43-50页

作者： richard salvi Center for Hearing and Deafness State University of New York at BuffaloBuffaloNew YorkUSA

Lead is a major environmental toxicant throughout the *** can induce severe neurotoxicity including irreversible hearing *** in vivo studies have shown that lead damages the auditory nervous system,but has little or no effect on cochlear sensory hair *** gain insights on lead ototoxic and neurotoxic effects in vitro,lead acetate (LA) was applied to postnatal day 3-4 rat cochlear organotypic cultures for 24 or 72 h with doses of 0.1,0.5,1,2 or 4 *** 24 or 72 h treatment with lead acetate,nearly all of cochlear sensory hair cells were ***,after 72 h treatment,the peripheral auditory nerve fibers projecting to the hair cells and the spiral ganglion neurons (SGN) were damaged when lead concentration exceeded 2 *** results indicated that 72 h treatment with only the high doses (> 2 mM) of lead actate damaged SGNs and peripheral nerve fibers;hair cells remained structurally intact even after 4 mM *** results show that lead primarily damages cochlear nerve fibers andSGNratherthanhaircells.

关键词： lead cochlea organotypic culture spiral ganglion neurons hair cells.

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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

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Migration of R28 Retinal Precursor Cells into Cochlear and Vestibular Organs

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Journal of Otology 2006年第1期1卷 51-56页

作者： Gail Seigel richard salvi Dept. of Ophthalmology University at Buffalo Center for Hearing & Deafness & Dept. of Communicative Disorders & Sciences University at Buffalo

Damaged hair cells and neurons in the inner ear generally can not be replaced in mammals. The loss of these cells causes permanent functional disorders in both the cochlear and vestibular systems. Transplantation of retinal precursor cells, R28 cells, into inner ear tissue may help replace missing cells. The aim of the current project was to induce R28 cell transdifferentiation into cochlear and vestibular cell types under culture conditions. The first part was related to R28 cell labeling with DiI fluorescence that would help identify and track R28 cells. The second part involved co-culturing R28 cells in cochlear and vestibular organotropic cultures or isolated spiral ganglion neurons. The results suggest that R28 cells have the potential to differentiate into supporting cell types and spiral ganglion neurons in serum free medium, probably under the influence of diffusible signals from inner ear tissues. This information is useful for future efforts in inducing stem cell differentiation in the inner ear to replace lost sensory and neural cells.

关键词： retinal precursor cells cochlea vestibule spiral ganglion neuron culture

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Gene expression in cisplatin ototoxicity and protection with p53 inhibitor

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Journal of Otology 2009年第2期4卷 61-70页

作者： Donald Coling richard salvi Center for Hearing & Deafness 137 Cary HallUniversity at Buffalo

Cisplatin damages cochlear hair cells and spiral ganglion neurons through cell death signaling pathways that are not fully understood. We used focused apoptosis gene microarrays to study early changes in gene expres- sion in cochlear cultures from P3 neonatal rats treated with cisplatin (0.2 mM). After 12 hours of cisplatin treat- ment, more than 50% of the 96 genes on the array showed a significant decrease in expression, consistent with widespread cell death. However, after 3 hours of cisplatin treatment, 10 genes showed significant increase in ex- pression in total cochlear tissue. In experiments with subsets of cochlear tissues, at 3h, cisplatin induced increased expression of 12 genes in the cochlear sensory epithelium (basilar membrane) and 11 genes in the spiral ganglion (tissue of Rosenthal’s canal, containing the spiral ganglion). These included pro- and anti-apoptotic genes in- volved in the p53 signaling pathway, TNF receptor family, NF-kappaB pathway, death domain family, death effec- tor domain family, Bcl-2 family, CARD family, TRAF family, and GTP signal transduction. Although the changes in gene expression showed an overlap between basilar membrane and spiral ganglion, other changes, which may reflect the unique response of each tissue, were also observed. Pifithrin-α blocked cisplatin-induced up-regulation of genes in the p53 signaling pathway when assayed by both superarray and real time PCR. The data add to our understanding of the involvement of p53 in cisplatin-induced ototoxicity and otoprotection, conferred by the p53 inhibitor Pifithrin-α.

关键词： cisplatin p53 Pifithrin-α gene expression ototoxicity cochlea hair cells spiral ganglion neurons

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Standardized surgical approaches to ear surgery in rats

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Journal of Otology 2015年第2期10卷 72-77页

作者： Peng Li Dalian Ding Kelei Gao richard salvi Department of Otolaryngology Head and Neck Surgery The Third Affiliated Hospital of Sun Yat-Sen University Center for Hearing and Deafness University of New York at Buffalo Department of Otolaryngology Head and Neck Surgery Xiangya Hospital Central South University

Objective： To describe several approaches of ear surgeries for experimental studies in rats. Methods： Anesthetized rats were prepared for demonstration of various ear surgery approaches designed to optimize experimental outcomes in studies with specific goals and exposure requirements. The surgical approaches included the posterior tympanum, superior tympanum, inferior tympanum and occipital approaches. Results： The middle ear cavity and inner ear were successfully exposed from different angles via the mentioned surgical approaches. For example, electrode placement for recording of cochlear bioelectric responses was easily achieved through the posterior tympanum or inferior tympanum approach. Alternatively, drug delivery or gene transfection via round window membrane was most easily accomplished using the posterior tympanum approach. Cochlear perfusion of protective or ototoxic drugs was best performed using the inferior tympanum approach. Ossicular chain interruption to induce a prolonged conductive hearing loss was readily achieved using a superior tympanum approach. Lastly, surgical destruction of the endolymphatic sac to induce experimental endolymphatic hydrops was readily performed via an occipital surgical ***： These standardized surgical approaches can be applied in scientific studies of the ear with different purposes covering electro- physiology, conductive hearing loss, intra-cochlear drug perfusion and experimental studies relevant to Meniere＇s disease.

关键词： Rat Middle ear Inner ear Surgical approach

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Characteristic anatomical structures of rat temporal bone

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Journal of Otology 2015年第3期10卷 118-124页

作者： Peng Li Kelei Gao Dalian Ding richard salvi Department of Otolaryngology Head and Neck SurgeryThe Third Affiliated HospitalSun Yat-Sen University Center for Hearing and Deafness State University of New York at Buffalo Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South University

As most gene sequences and functional structures of internal organs in rats have been well studied,rat models arc widely used in experimental medical studies.A large number of descriptions and atlas of the rat temporal bone have been published,but some detailed anatomy of its surface and inside structures remains to be *** focusing on some unique characteristics of the rat temporal bone,the current paper aims to provide more accurate and detailed information on rat temporal bone anatomy in an attempt to complete missing or unclear areas in the existed *** also hope this paper can lay a solid foundation for experimental rat temporal bone surgeries,and promote information exchange among colleagues,as well as providing useful guidance for novice researchers in the field of hearing research involving rats.

关键词： Rat Temporal bone Anatomy

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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

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Ototoxic destruction by co-administration of kanamycin and ethacrynic acid in rats

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2011年第10期12卷 853-861页

作者： Hong LIU Da-lian D1NG Hai-yan JIANG Xue-wen WU richard salvi Hong SUN Center for Hearing and Deafness University at Buffalo State University of New York New York 14214 USA Department of Otolaryngology the Third Xiangya Hospital of Central South University Changsha 410013 China Department of Otolaryngology Xiangya Hospital of Central South University Changsha 410008 China

It is well known that ethacrynic acid (EA) can potentiate the ototoxicity of aminoglycoside antibiotics (AmAn) such as kanamycin (KM),if they were applied at the same ***,to create the model of EA-KMinduced cochlear lesion in rats,adult rats received a single injection of EA (75 mg/kg,intravenous injection),or followed immediately by KM (500 mg/kg,intramuscular injection).The hearing function was assessed by auditory brainstem response (ABR) measurement in response to click and/or tone bursts at 4,8,12,16,20,24,and 32 *** static microcirculation status in the stria vascularis after a single EA injection was evaluated with eosin *** pathological changes in cochlear and vestibular hair cells were also quantified after co-administration of EA and *** a single EA injection,blood flow in vessels supplying the stria vascularis rapidly ***,the blood supply to the cochlear lateral wall partially recovered 5 h after EA *** changes in ABR were basically parallel to the microcirculation changes in stria vascularis after single EA ***,disposable co-administration of EA and KM resulted in a permanent hearing loss and severe damage to the cochlear hair cells,but spared the vestibular hair *** the cochlear lateral wall is the important part of the blood-cochlea barrier,EA-induced anoxic damage to the epithelium of stria vascularis may enhance the entry of KM to the ***,experimental animal model of selective cochlear damage with normal vestibular systems can be reliably created through co-administration of EA and KM.

关键词： Ototoxicity Ethacrynic acid Kanamycin Rat Blood-cochlea barrier

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