Pharmacological protection of hearing loss in the mouse model of endolymphatic hydrops

Melki, Sami; Heddon, Chris; Frankel, Jonathan K.; Levitt, Alex; Momin, Suhael; Alagramam, Kumar N.; Megerian, Cliff A.

doi:10.1002/lary.21018

Cited by 15 publications

(14 citation statements)

References 31 publications

(40 reference statements)

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“…Their data show a significant improvement of cochlear function index in both experimental drug groups compared to untreated Hyp-Duk/Y mice at P21 and P25 ( p < 0.001 in both, respectively). There was no synergistic effect of adding riluzole to DMSO, compared to DMSO alone [64]. This study supports the theory of excitotoxicity and/or ROS as a step in ELH-associated hearing loss and demonstrates potential for oto-protective drug therapy.…”

Section: Therapeutic Implicationssupporting

confidence: 75%

A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse

Wick

Semaan

Zheng

et al. 2014

Curr Otorhinolaryngol Rep

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Animal models of endolymphatic hydrops (ELH) provide critical insight into the pathophysiology of Meniere’s disease (MD). A new genetic murine model, called the Phex mouse, circumvents prior need for a time and cost-intensive surgical procedure to create ELH. The Phex mouse model of ELH, which also has X-linked hypophosphatemic rickets, creates a postnatal, spontaneous, and progressive ELH whose phenotype has a predictable decline of vestibular and hearing function reminiscent of human MD. The Phex mouse enables real-time histopathologic analysis to assess diagnostic and therapeutic interventions as well as further our understanding of ELH’s adverse effects. Already the model has validated electrocochleography and cervical vestibular evoked myogenic potential as useful diagnostic tools. New data on caspase activity in apoptosis of the spiral ganglion neurons may help target future therapeutic interventions. This paper highlights the development of the Phex mouse model and highlights its role in characterizing ELH.

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Section: Therapeutic Implicationssupporting

confidence: 75%

A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse

Wick

Semaan

Zheng

et al. 2014

Curr Otorhinolaryngol Rep

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“…Ménière's disease (MD) is characterized by the triad of fluctuating hearing loss, episodic vertigo and tinnitus, and by endolymphatic hydrops found on post-mortem examination [1,2]. The cause of Meniere's disease remains unclear, although numerous causative factors have been considered in the development of hydrops and in the pathogenesis of related cochleovestibular dysfunction [3].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress, Redox Homeostasis and Cellular Stress Response in Ménière’s Disease: Role of Vitagenes

et al. 2010

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Ménière's disease (MD) is characterized by the triad of fluctuating hearing loss, episodic vertigo and tinnitus, and by endolymphatic hydrops found on post-mortem examination. Increasing evidence suggests that oxidative stress is involved in the development of endolymphatic hydrops and that cellular damage and apoptotic cell death might contribute to the sensorineural hearing loss found in later stages of MD. While excess reactive oxygen species (ROS) are toxic, regulated ROS, however, play an important role in cellular signaling. The ability of a cell to counteract stressful conditions, known as cellular stress response, requires the activation of pro-survival pathways and the production of molecules with anti-oxidant, anti-apoptotic or pro-apoptotic activities. Among the cellular pathways conferring protection against oxidative stress, a key role is played by vitagenes, which include heat shock proteins (Hsps) as well as the thioredoxin/thioredoxin reductase system. In this study we tested the hypothesis that in MD patients measurable increases in markers of cellular stress response and oxidative stress in peripheral blood are present. This study also explores the hypothesis that changes in the redox status of glutathione, the major endogenous antioxidant, associated with abnormal expression and activity of carbonic anhydrase can contribute to increase oxidative stress and to disruption of systemic redox homeostasis which can be associated to possible alterations on vulnerable neurons such as spiral ganglion neurons and consequent cellular degeneration. We therefore evaluated systemic oxidative stress and cellular stress response in patients suffering from Meniere's disease (MD) and in age-matched healthy subjects. Systemic oxidative stress was estimated by measuring protein oxidation, such as protein carbonyls (PC) and 4-hydroxynonenal (HNE) in lymphocytes of MD patients, as well as ultraweak luminescence (UCL) as end-stable products of lipid oxidation in MD plasma and lymphocytes, as compared to age-matched controls, whereas heat shock proteins Hsp70 and thioredoxin (Trx) expression were measured in lymphocytes to evaluate the systemic cellular stress response. Increased levels of PC (P < 0.01) and HNE (P < 0.05) have been found in lymphocytes from MD patients with respect to control group. This was paralleled by a significant induction of Hsp70, and a decreased expression of Trx (P < 0.01), whereas a significant decrease in both plasma and lymphocyte ratio reduced glutathione GSH) vs. oxidized glutathione (GSSG) (P < 0.05) were also observed. In conclusion, patients affected by MD are under condition of systemic oxidative stress and the induction of vitagenes Hsp70 is a maintained response in counteracting the intracellular pro-oxidant status generated by decreased content of GSH as well as expression of Trx. The search for novel and more potent inducers of vitagenes will facilitate the development of pharmacological strategies to increase the intrinsic capacity of vulnerable ganglion cells to maximize antid...

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“…The amount of damage is associated with amount of hearing loss in endolymphatic hydrops animal models (46). Dimethyl sulfoxide, a drug with antiinflammatory properties, was successfully used in a single study to protect against neuronal damage and associated hearing loss in animals with surgically induced hydrops (15,47) or in animals which are genetically predispositioned to develop hydrops (15). One could say that some sort of spiral ganglion damage is associated with hydrops, primarily in the apical region, but the mechanism of ganglion cell death in MD remains an open question.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, increased oxidative stress, such as upregulated reactive oxygen species, was observed in a sample of patients with MD (14). Endolymphatic hydrops animal models have provided support for inflammatory processes involved in the hearing loss observed in MD and hydrops (15).…”

mentioning

confidence: 91%

Oral Steroid Treatment for Hearing Improvement in Ménière’s Disease and Endolymphatic Hydrops

Fisher¹,

Derebery²,

Friedman³

2012

Otology & Neurotology

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The results of this and other studies would indicate that a Ménière's disease or endolymphatic hydrops patient is unlikely to experience an improvement in hearing from a short course of oral steroid. Clinically observed temporary improvement did not sustain over several months. Further work to elucidate the mechanisms underlying hearing loss in hydrops, perhaps focusing on the dendrite damage noted in animal models of hydrops, is warranted.

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Pharmacological protection of hearing loss in the mouse model of endolymphatic hydrops

Abstract: This study demonstrates pharmacological hearing protection in an animal model of ELH. The results support the assertion that inflammatory (reactive oxygen species) injury, which is part of the excitotoxic pathway, contributes to the development of ELH-associated hearing loss.

Cited by 15 publications

References 31 publications

A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse

A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse

Oxidative Stress, Redox Homeostasis and Cellular Stress Response in Ménière’s Disease: Role of Vitagenes

Oral Steroid Treatment for Hearing Improvement in Ménière’s Disease and Endolymphatic Hydrops

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