Tauroursodeoxycholic acid prevents hearing loss and hair cell death in Cdh23 mice

Hu, Jiaqi; Xu, Min; Yuan, Jing; Li, B.; Entenman, Shami; Yu, Huan; Zheng, Qing Yin

doi:10.1016/j.neuroscience.2015.12.050

Cited by 17 publications

(10 citation statements)

References 38 publications

(57 reference statements)

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“…Erl mice have the Cdh23 erl/erl mutation which confers non-syndromic autosomal recessive deafness by altering the CDH23 protein in the upper part of the tip-link in HCs. These mice were a novel tool in assessing otoprotective drugs because of the time frame from the initiation of HC death to when complete deafness occurs (Hu et al, 2016 ). The experiments showed that the TUDCA-treated mice had significantly preserved as hearing determined by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) tests possibly due to the downregulation of caspase-3 and caspase-9 which was determined using western blot studies (Hu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…These mice were a novel tool in assessing otoprotective drugs because of the time frame from the initiation of HC death to when complete deafness occurs (Hu et al, 2016 ). The experiments showed that the TUDCA-treated mice had significantly preserved as hearing determined by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) tests possibly due to the downregulation of caspase-3 and caspase-9 which was determined using western blot studies (Hu et al, 2016 ). TUDCA’s efficacy was also tested in gentamicin induced ototoxicity using both mouse primary OC explant cultures and an OC cell line, HEI-OC1.…”

Section: Discussionmentioning

confidence: 99%

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Evaluating the Efficacy of Taurodeoxycholic Acid in Providing Otoprotection Using an in vitro Model of Electrode Insertion Trauma

Shah

Mittal

Shahal

et al. 2020

Front. Mol. Neurosci.

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Cochlear implants (CIs) are widely used to provide auditory rehabilitation to individuals having severe to profound sensorineural hearing loss (SNHL). However, insertion of electrode leads to inner trauma and activation of inflammatory and apoptotic signaling cascades resulting in loss of residual hearing in implanted individuals. Pharmaceutical interventions that can target these signaling cascades hold great potential for preserving residual hearing by preventing sensory cell damage. Bile salts have shown efficacy in various regions of the body as powerful antioxidants and anti-inflammatory agents. However, their efficacy against inner ear trauma has never been explored. The objective of this study was to determine whether taurodeoxycholic acid (TDCA), a bile salt derivative, can prevent sensory cell damage employing an in vitro model of electrode insertion trauma (EIT). The organ of Corti (OC) explants were dissected from postnatal day 3 (P-3) rats and placed in serum-free media. Explants were divided into control and experimental groups: (1) untreated controls; (2) EIT; (3) EIT+ TDCA (different concentrations). Hair cell (HC) density, analyses of apoptosis pathway (cleaved caspase 3), levels of reactive oxygen species (ROS) as well as inducible nitric oxide synthase (iNOS) activity and Mitochondrial Membrane Potential (MMP) were assayed. Treatment with TDCA provided significant otoprotection against HC loss in a dose-dependent manner. The molecular mechanisms underlying otoprotection involved decreasing oxidative stress, lowering levels of iNOS, and abrogating generation of cleaved caspase 3. The results of the present study suggest that TDCA provides efficient otoprotection against EIT, in vitro and should be explored for developing pharmaceutical interventions to preserve residual hearing post-cochlear implantation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluating the Efficacy of Taurodeoxycholic Acid in Providing Otoprotection Using an in vitro Model of Electrode Insertion Trauma

Shah

Mittal

Shahal

et al. 2020

Front. Mol. Neurosci.

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“…A growing body of evidence suggests that TUDCA alleviates ER stress by enhancing the capacity of folding enzymes in the ER or by regulating Ca 2+ homeostasis in the ER [Vega et al, 2016]. In addition, TUDCA ameliorates numerous types of ER stress-related diseases [Hetz et al, 2013], including various types of hearing loss [Hu et al, 2016b;Oishi et al, 2015]. In our study, we not only observed the induction of ER stress in cochlear cells following cisplatin treatment but also confirmed the alleviating effect of the classical proteostasis promoter TUDCA on cisplatin-induced ototoxicity ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

Zong¹,

Liu²,

Wan³

et al. 2017

Audiol Neurotol

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Endoplasmic reticulum (ER) stress arises when excessive improperly folded proteins accumulate in the ER lumen. When ER stress occurs, the unfolded protein response (UPR) is subsequently activated to restore ER proteostasis. However, severe ER stress leads to apoptosis. Recent studies have suggested that cisplatin cytotoxicity may be related to ER stress. The purpose of this study was to determine whether ER stress participates in cochlear cell apoptosis in a cisplatin-induced ototoxicity rat model and to also determine the possible relationship between ER stress and hearing loss. Our results revealed that treatment with cisplatin upregulated the expression of active caspase-12 in cochlear cells, which is indicative of cisplatin-induced activation of ER-specific apoptosis. Increased expression of C/EBP homologous protein (CHOP) and cleaved caspase-9 suggested a close relationship between severe ER stress and mitochondria-dependent apoptosis in the cochlear cells of cisplatin-treated rats. In addition, we found that tauroursodeoxycholic acid (TUDCA), a promoter of ER proteostasis, had a protective effect on cisplatin-induced hearing loss. These results demonstrate that ER stress is involved in the cisplatin-induced apoptosis of cochlear cells in vivo.

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“…OHC was counted as present if V-shape of hair bundles was intact. Counts of OHC in three continuous views for each turn of a cochlea were recorded and analysed [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Hearing Improvement in A/J Mice via the Mouse Nerve Growth Factor

Gao

Xie

et al. 2017

Clin Exp Otorhinolaryngol

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Objectives To investigate the otoprotective effects of mouse nerve growth factor (mNGF) in A/J mice.Methods The mice at postnatal day 7 (P7) were randomly separated into a mNGF treated group (mNGF group) and a distilled water (for injection) treated group (control group). The mNGF dissolved in distilled water or distilled water alone was given to the mice once every other day from P7 by intramuscular injection in the hips. The otoprotective effects of mNGF in A/J mice were observed in a time course manner. The thresholds of auditory-evoked brainstem response (ABR) were tested from the age of the 3rd to the 8th week. Sections of the inner ears were stained by hematoxylin and eosin, and spiral ganglion neurons (SGNs) were observed at the age of the 3rd, the 6th,and the 8th week. Counts of whole mount outer hair cells (OHCs) in the cochleae were made at the age of 8 weeks. Expression of apoptosis related genes was determined by quantitative real-time polymerase chain reaction and Western blotting.Results ABR thresholds of the mNGF group were significantly lower than those of the control group at the age of the 6th and the 8th week. Moreover, the mNGF preserved OHC and SGN in the mouse cochleae in this period. Further experiments showed that the expression of caspase genes (including caspase-3) was inhibited in the mouse inner ears in the mNGF group.Conclusion The mNGF improves hearing in A/J mice by preserving SGN and OHC in the cochleae.

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Tauroursodeoxycholic acid prevents hearing loss and hair cell death in Cdh23 mice

Cited by 17 publications

References 38 publications

Evaluating the Efficacy of Taurodeoxycholic Acid in Providing Otoprotection Using an in vitro Model of Electrode Insertion Trauma

Evaluating the Efficacy of Taurodeoxycholic Acid in Providing Otoprotection Using an in vitro Model of Electrode Insertion Trauma

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

Hearing Improvement in A/J Mice via the Mouse Nerve Growth Factor

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