Therapeutics of hearing loss: expectations vs reality

Atar, Orna; Avraham, Karen B.

doi:10.1016/s1359-6446(05)03618-4

Cited by 30 publications

(19 citation statements)

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“…It has been noted that different etiologies of SNHL such as aging and drug toxicity have similar cellular and molecular mechanisms where a final common pathway is apoptosis [29]. There is also compelling evidence implicating ROS in the damage associated with cochlear ischemia, noise trauma, presbycusis, meningitis-associated hearing loss and aminoglycoside and CDDP ototoxicity [30].…”

Section: Discussionmentioning

confidence: 99%

Dose-dependant radiation-induced apoptosis in a cochlear cell-line

et al. 2006

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Cisplatin and gentamycin are both ototoxic and they have been shown to induce cochlear cell apoptosis. Although radiation is also ototoxic, radiation-induced apoptosis in cochlear cells has not been studied. This study aimed to investigate the biophysical changes of dose-related radiation-induced cochlear cell apoptosis in an experimental model. Post gamma-irradiation apoptosis was demonstrated in the cochlear cell-line OC-k3 by flow cytometry and TUNEL assay. This was dose-dependant with enhanced apoptosis resulting after 20 than 5 Gy, and occurred predominantly at 72 h post-irradiation. Microarray analysis showed associated dose-dependant apoptotic gene regulation changes. Western blotting revealed p53 up-regulation of at 72 h and phosphorylation at 3, 24, 48 and 72 h after irradiation. Early activation of c-jun occurred at 3 h, but was not sustained with time. Associated dose-dependant intracellular generation of reactive oxygen species (ROS) was also demonstrated using 2', 7'-dichlorofluorescein diacetate. In conclusion, this study demonstrated a dose-dependant cochlear cell apoptosis and associated ROS generation after irradiation, with p53 possibly playing a key role. Based on this ROS-linked apoptotic model, anti-oxidants and anti-apoptotic factors could potentially be used to prevent radiation-induced sensori-neural hearing loss. As these medications can be delivered topically through the middle ear, their systematic side effects could therefore be minimized.

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Section: Discussionmentioning

confidence: 99%

Dose-dependant radiation-induced apoptosis in a cochlear cell-line

et al. 2006

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Section: Nerve Growth Factor and Neurotrophinsmentioning

confidence: 84%

“…Neurons differentiated from human progenitors co-express receptors for neurotrophic factors such as TrkB and TrkC (Rask-Andersen et al, 2005), consistent with the co-expression of these receptors in auditory neurons (Pirvola et al, 1992;Farinas et al, 2001). On this basis, neurotrophic factors have been proposed as candidates for pharmacological treatment to prevent secondary auditory nerve degeneration and to promote neurite re-growth following hearing loss (reviewed in Atar and Avraham, 2005;Holley, 2005).All neurotrophins bind to p75 NTR , which also interacts with Trk receptors to modulate ligand binding specificity, affinity, and function in certain cell types (Benedetti et al, 1993;Bibel et al, 1999). Mature neurotrophins preferentially bind to Trk receptors whereas the immature "proforms" of these proteins have higher affinity for p75 NTR , which fulfils a critical role in controlling the balance between cell survival/death.…”

mentioning

confidence: 80%

A network of growth and transcription factors controls neuronal differentation and survival in the developing ear

Sánchez-Calderón¹,

Milo²,

León³

et al. 2007

Int. J. Dev. Biol.

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Inner ear neurons develop from the otic placode and connect hair cells with central neurons in auditory brain stem nuclei. Otic neurogenesis is a developmental process which can be separated into different cellular states that are characterized by a distinct combination of molecular markers. Neurogenesis is highly regulated by a network of extrinsic and intrinsic factors, whose participation in auditory neurogenesis is discussed. Trophic factors include the fibroblast growth factor, neurotrophins and insulin-like peptide families. The expression domains of transcription factor families and their roles in the regulation of intracellular signaling pathways associated with neurogenesis are also discussed. Understanding and defining the key factors and gene networks in the development and function of the inner ear represents an important step towards defeating deafness. KEY WORDS: otic neurogenesis, IGF-I, FGF, inner ear, auditory ganglion, cochlear microarray Otic neurogenesisThe inner ear develops from the otic placode, an ectodermal patch located close to the neural tube that invaginates to form a transitory structure, the otic cup. This cup subsequently closes and pinches off from the ectoderm to generate the otic vesicle ( Figure 1). The otic vesicle is an autonomous structure that contains the information required to generate most of the cell types and structures of the adult inner ear (Bissonnette and Fekete, 1996;Bever et al., 2003; reviewed in Varela-Nieto et al., 2004). The mammalian inner ear is composed of six distinct sensory organs: the three cristae of the semicircular canal, the two maculae of the saccule and utricle and the organ of Corti in the cochlea. The cristae and the maculae are vestibular organs, whereas the organ of Corti is the organ of hearing (reviewed in Moller, 2006). The inner ear cochlear ganglion is formed by bipolar neurons that connect the peripheral sensory receptors or hair cells with central neurons in auditory brain stem nuclei. The correct organogenesis of the inner ear involves a dynamic balance of cell proliferation, differentiation, survival and death, processes that are tightly regulated by a network of extrinsic and intrinsic factors (Frago et al., 2000;Varela-Nieto et al., 2003 andLeon et al., 2004).The process of otic neurogenesis can be separated into different cellular states, each characterized by a distinct combination of molecular markers (summarized in Figure 1A). The first Int. J. Dev. Biol. 51: 557-570 (2007) doi: 10.1387/ijdb.072373hs visible output of otic neurogenesis is the delamination of neural cells (otic neuroblasts) from the otic cup (Fig. 1B). These neuroblasts are committed to generate otic neurons and they populate the cochleo-vestibular ganglion (CVG). This ganglion is generated from a region of the otic vesicle epithelium denominated the prospective neural-sensorial domain and that is defined by the domain in which Ngn1 and Deltal1 are co-expressed at early stages (Adam et al., 1998;Abu-Elmagd et al., 2001). It is believed that both n...

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“…It is believed that etiologies of SNHL such as ageing and drug toxicity, share similar cell death mechanisms leading to a final common apoptotic pathway (Atar et al, 2005). Radiation-induced apoptosis has been well demonstrated in non-cochlear cell systems and is generally accepted as an important mechanism of radiation-induced cell death in vivo (Shinomiya 2001;Verheij & Bartelink 2000) Therefore, by relating our findings to what is already known, it is not unreasonable to expect radiation-induced apoptosis occurring in cochlear hair-cells in vivo.…”

Section: Pathogenesismentioning

confidence: 99%