Dose-dependent cochlear and vestibular toxicity of trans-tympanic cisplatin in the rat

Callejo, Àngela; Durochat, Amandine; Bressieux, Stéphanie; Saleur, Aurélie; Chabbert, Christian; Juan, Ivan Doménech; Llorens, Jordi; Gaboyard-Niay, Sophie

doi:10.1016/j.neuro.2017.02.007

Cited by 19 publications

(14 citation statements)

References 57 publications

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“…The specific roles of Anxa4 are somewhat unclear, although other Annexins play a role in shuttling specific molecules to the plasma or nuclear membrane ( Bandorowicz-Pikula et al, 2012 ; Domon et al, 2012 ). Interestingly, elevated Anxa4 levels have been correlated with resistance to platinum-based chemotherapy drugs ( Matsuzaki et al, 2014 ; Morimoto et al, 2014 ), suggesting that at least some of the heterogeneity in vestibular HC death in response to cisplatin-treatment ( Callejo et al, 2017 ; Cunningham and Brandon, 2006 ) could be a result of expression of Anxa4 in Type II HCs. Consistent with this hypothesis, Type II HCs show greater resistance by comparison with Type I HCs following cisplatin treatment in vitro (L.L.…”

Section: Discussionmentioning

confidence: 99%

Characterization of spatial and temporal development of Type I and Type II hair cells in the mouse utricle using new cell-type-specific markers

2018

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The utricle of the inner ear, a vestibular sensory structure that mediates perception of linear acceleration, is comprised of two morphologically and physiologically distinct types of mechanosensory hair cells, referred to as Type Is and Type IIs. While these cell types are easily discriminated in an adult utricle, understanding their development has been hampered by a lack of molecular markers that can be used to identify each cell type prior to maturity. Therefore, we collected single hair cells at three different ages and used single cell RNAseq to characterize the transcriptomes of those cells. Analysis of differential gene expression identified Spp1 as a specific marker for Type I hair cells and Mapt and Anxa4 as specific markers for Type II hair cells. Antibody labeling confirmed the specificity of these markers which were then used to examine the temporal and spatial development of utricular hair cells. While Type I hair cells develop in a gradient that extends across the utricle from posterior-medial to anterior-lateral, Type II hair cells initially develop in the central striolar region and then extend uniformly towards the periphery. Finally, by combining these markers with genetic fate mapping, we demonstrate that over 98% of all Type I hair cells develop prior to birth while over 98% of Type II hair cells develop post-natally. These results are consistent with previous findings suggesting that Type I hair cells develop first and refute the hypothesis that Type II hair cells represent a transitional form between immature and Type I hair cells.

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Section: Discussionmentioning

confidence: 99%

Characterization of spatial and temporal development of Type I and Type II hair cells in the mouse utricle using new cell-type-specific markers

2018

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“…For example, Sergi et al (2003) observed significant functional declines in the guinea pig vestibulo-ocular reflex accompanied by significant losses of Type I and Type II VHCs in cisplatin-treated guinea pigs relative to controls following systemic cisplatin administration (2.5 mg/kg/day for 6 days). Callejo et al (2017) reported significant dose-dependent vestibular dysfunction using behavioral tasks in rats treated transtympanically with cisplatin. The differences in animal model (guinea pig and rat versus mouse), the delivery route (transtympanic versus systemic), the dosing schedule (6 consecutive days versus 3 cycles of 4 days of drug injection) and the functional assays used to assess different elements of the vestibular system (semicircular canals versus otolith organs) likely to account for the differing degrees of reported vestibulotoxicity.…”

Section: Discussionmentioning

confidence: 99%

An optimized, clinically relevant mouse model of cisplatin-induced ototoxicity

et al. 2019

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Cisplatin-induced ototoxicity results in significant, permanent hearing loss in pediatric and adult cancer survivors. Elucidating the mechanisms underlying cisplatin-induced hearing loss as well as the development of therapies to reduce and/or reverse cisplatin ototoxicity have been impeded by suboptimal animal models. Clinically, cisplatin is most commonly administered in multi-dose, multi-cycle protocols. However, many animal studies are conducted using single injections of high-dose cisplatin, which is not reflective of clinical cisplatin administration protocols. Significant limitations of both high-dose, single-injection protocols and previous multi-dose protocols in rodent models include high mortality rates and relatively small changes in hearing sensitivity. These limitations restrict assessment of both long-term changes in hearing sensitivity and effects of potential protective therapies. Here, we present a detailed method for an optimized mouse model of cisplatin ototoxicity that utilizes a multi-cycle administration protocol that better approximates the type and degree of hearing loss observed clinically. This protocol results in significant hearing loss with very low mortality. This mouse model of cisplatin ototoxicity provides a platform for examining mechanisms of cisplatin-induced hearing loss as well as developing therapies to protect the hearing of cancer patients receiving cisplatin therapy.

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“…Bilateral vestibular failure (BVF) is characterized by unsteadiness of stance and gait and disabling oscillopsia during head movements ( 1 ). BVF has a wide spectrum of etiologies ( 2 , 3 ), ranging from vestibulo-toxic agents such as antibiotics ( 4 , 5 ), opioids ( 6 ), salicyl acid ( 7 ), amiodarone ( 8 ) and chemotherapy ( 9 , 10 ); and polyneuropathies ( 11 – 13 ) to sequential vestibulopathies, e.g., due to Menière’s disease or vestibular neuritis. Most often BVF remains idiopathic.…”

Section: Introductionmentioning

confidence: 99%

Postural Control in Bilateral Vestibular Failure: Its Relation to Visual, Proprioceptive, Vestibular, and Cognitive Input

et al. 2017

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Patients with bilateral vestibular failure (BVF) suffer from postural and gait unsteadiness with an increased risk of falls. The aim of this study was to elucidate the differential role of otolith, semicircular canal (SSC), visual, proprioceptive, and cognitive influences on the postural stability of BVF patients. Center-of-pressure displacements were recorded by posturography under six conditions: target visibility; tonic head positions in the pitch plane; horizontal head shaking; sensory deprivation; dual task; and tandem stance. Between-group analysis revealed larger postural sway in BVF patients on eye closure; but with the eyes open, BVF did not differ from healthy controls (HCs). Head tilts and horizontal head shaking increased sway but did not differ between groups. In the dual task condition, BVF patients maintained posture indistinguishable from controls. On foam and tandem stance, postural sway was larger in BVF, even with the eyes open. The best predictor for the severity of bilateral vestibulopathy was standing on foam with eyes closed. Postural control of our BVF was indistinguishable from HCs once visual and proprioceptive feedback is provided. This distinguishes them from patients with vestibulo-cerebellar disorders or functional dizziness. It confirms previous reports and explains that postural unsteadiness of BVF patients can be missed easily if not examined by conditions of visual and/or proprioceptive deprivation. In fact, the best predictor for vestibular hypofunction (VOR gain) was examining patients standing on foam with the eyes closed. Postural sway in that condition increased with the severity of vestibular impairment but not with disease duration. In the absence of visual control, impaired otolith input destabilizes BVF with head retroflexion. Stimulating deficient SSC does not distinguish patients from controls possibly reflecting a shift of intersensory weighing toward proprioceptive-guided postural control. Accordingly, proprioceptive deprivation heavily destabilizes BVF, even when visual control is provided.

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Dose-dependent cochlear and vestibular toxicity of trans-tympanic cisplatin in the rat

Cited by 19 publications

References 57 publications

Characterization of spatial and temporal development of Type I and Type II hair cells in the mouse utricle using new cell-type-specific markers

Characterization of spatial and temporal development of Type I and Type II hair cells in the mouse utricle using new cell-type-specific markers

An optimized, clinically relevant mouse model of cisplatin-induced ototoxicity

Postural Control in Bilateral Vestibular Failure: Its Relation to Visual, Proprioceptive, Vestibular, and Cognitive Input

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