Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Roy, Soumen; Ryals, Matthew; Bruele, Astrid Botty Van den; Fitzgerald, Tracy S.; Cunningham, Lisa L.

doi:10.1172/jci71353

Cited by 65 publications

(67 citation statements)

References 29 publications

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“…Mice were 2 months old at the beginning of each injection protocol, which has been described. 49 Briefly, cisplatin (APP Pharmaceuticals, LLC) was administered via intraperitoneal injection, 4 mg/kg each day for 4 days, followed by 10 days of recovery. Three such cycles of cisplatin were administered.…”

Section: Methodsmentioning

confidence: 99%

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Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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Hearing loss and balance disorders affect millions of people worldwide. Sensory transduction in the inner ear requires both mechanosensory hair cells (HCs) and surrounding glia-like supporting cells (SCs). HCs are susceptible to death from aging, noise overexposure, and treatment with therapeutic drugs that have ototoxic side effects; these ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic drug cisplatin. Although both classes of drugs are known to kill HCs, their effects on SCs are less well understood. Recent data indicate that SCs sense and respond to HC stress, and that their responses can influence HC death, survival, and phagocytosis. These responses to HC stress and death are critical to the health of the inner ear. Here we have used live confocal imaging of the adult mouse utricle, to examine the SC responses to HC death caused by aminoglycosides or cisplatin. Our data indicate that when HCs are killed by aminoglycosides, SCs efficiently remove HC corpses from the sensory epithelium in a process that includes constricting the apical portion of the HC after loss of membrane integrity. SCs then form a phagosome, which can completely engulf the remaining HC body, a phenomenon not previously reported in mammals. In contrast, cisplatin treatment results in accumulation of dead HCs in the sensory epithelium, accompanied by an increase in SC death. The surviving SCs constrict fewer HCs and display impaired phagocytosis. These data are supported by in vivo experiments, in which cochlear SCs show reduced capacity for scar formation in cisplatin-treated mice compared with those treated with aminoglycosides. Together, these data point to a broader defect in the ability of the cisplatin-treated SCs, to preserve tissue health in the mature mammalian inner ear. . 4 SCs perform many functions, including providing critical trophic factors, preventing excitotoxicity, and mediating regeneration in those systems (non-mammalian vertebrates) capable of replacing lost HCs. 5-11 When HCs die, SCs also preserve the integrity and function of the remaining tissue by forming scars and clearing dead HCs. 2,12-17 Maintaining a fluid barrier at the surface of the sensory epithelium after damage is necessary to preserve the electro-chemical gradient that drives HC depolarization and therefore sensory transduction after the onset of hearing (reviewed in Wangemann). 18 Several major stressors cause HC death, 19-22 including aging, noise trauma, and exposure to therapeutic drugs with ototoxic side effects. When a HC is killed by noise or aminoglycoside antibiotics, surrounding SCs form a filamentous actin (F-actin) cable that constricts the HC at its apex. 2,[12][13][14][15][16][17] This process separates the apical portion of the cell, including the stereocilia bundle, from the HC body and preserves a sealed reticular lamina. 23 In the chick utricle, following the apical constriction of dead HCs, the SCs engulf and phagocytose the remaining HC corpse. 15 Additional data from the chick indicate that the ototoxi...

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Section: Methodsmentioning

confidence: 99%

“…Preand post-injection auditory brainstem response (ABR) testing was performed to examine hearing sensitivity in both cisplatin-and kanamycin-treated groups, as described. 49 ABR testing was also performed for each control group.…”

Section: Methodsmentioning

confidence: 99%

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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“…A new approach called sound preconditioning has been developed to inhibit cisplatin-induced hearing loss (Roy et al, 20 13). Cochlear expression of heat shock proteins (HSPs) can be induced by sound stimuli and are protective against cisplatin ototoxicity in mouse models of cisplatin-induced hearing loss.…”

Section: Risk Factors That Enhance Cisplatin Toxicitymentioning

confidence: 99%

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

2015

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Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.

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“…Previously, we showed that heat shock inhibits both cisplatin-and aminoglycoside-induced hair cell death (Cunningham and Brandon 2006). In addition to heat shock, noise exposure has also been shown to induce HSPs in the inner ear (Matsunobu et al 2009;Roy et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Cited by 65 publications

References 29 publications

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

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