Novel oral multifunctional antioxidant prevents noise-induced hearing loss and hair cell loss

Chen, G.D.; Daszynski, D.M.; Ding, Dalian; Jiang, Haiyan; Woolman, Theodor A; Blessing, K.; Kador, Peter F.; Salvi, Richard

doi:10.1016/j.heares.2019.107880

Cited by 30 publications

(33 citation statements)

References 52 publications

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“…The clinical consequences of IHC and SGN degeneration is that it greatly reduces the benefits of hearing aids and cochlear implants for patients receiving HPβCD treatments. Given that the delayed degeneration of IHCs, ANFs, and SGNs occurs over a well-defined 4- to 8-week time window following HBβCD treatment, researchers could use this animal model to test out various therapeutic interventions to prevent the secondary degeneration of the remaining IHC, ANFs and SGNs using antioxidants, neurotrophins or a cocktail of the two ( Rybak and Whitworth, 2005 ; Atkinson et al, 2012 ; Leake et al, 2019 ; Chen et al, 2020 ). The optimal time for delivering these therapies would seem to be from approximately 7-days after HPβCD treatment to 8-weeks post-treatment and possibly longer.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

Ding¹,

Jiang²,

Manohar³

et al. 2021

Front. Cell Dev. Biol.

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2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4–6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

Ding¹,

Jiang²,

Manohar³

et al. 2021

Front. Cell Dev. Biol.

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“…Such reports support the hypothesis that therapeutic strategies targeting free radical overproduction are potentially useful to ameliorate the damaging effect of noise on hearing, which leads to cell death, mostly apoptotic ( Figure 2 ). For instance, experimental studies that involve glutathione (Yamasoba et al, 1998 ; Ohinata et al, 2000 ; Hight et al, 2003 ; Henderson et al, 2006 ), N-acetylcysteine (Kopke et al, 2000 , 2007 ), glutathione synthetic enzymes (Kil et al, 2007 , 2017 ), multifunctional antioxidants (Chen et al, 2020 ) or micronutrients (Le Prell et al, 2007a , b ) suggest attenuation of cochlear damage and/or reduction of the threshold shifts following noise exposure.…”

Section: Oxidative Stress and Antioxidantsmentioning

confidence: 99%

“…Interestingly, recent evidence suggests that HK-2, a multifunctional antioxidant with a metal chelator and free radical scavenger properties (Kawada and Kador, 2015 ; Kawada et al, 2015 ; Chen et al, 2020 ), is effective in treating NIHL. Oral administration of HK-2 to Sprague-Dawley rats 10 days before noise over-exposure exerts a significant protective effect in the cochlea, not only enhancing hair cell survival but also reducing the auditory threshold shifts when compared to untreated rats.…”

Section: Oxidative Stress and Antioxidantsmentioning

confidence: 99%

“…Oral administration of HK-2 to Sprague-Dawley rats 10 days before noise over-exposure exerts a significant protective effect in the cochlea, not only enhancing hair cell survival but also reducing the auditory threshold shifts when compared to untreated rats. While oral intake 10 days after noise exposure did not improve overall cell survival, it still preserved auditory function (Chen et al, 2020 ), suggesting a mild protective effect of HK-2 when taken several days after the exposure. Given that HK-2 is efficient at reducing noise-induced cell damage, it could be administered orally and it shows no side effects, at least in rats, it has been suggested as a new treatment option for NIHL (Chen et al, 2020 ).…”

Section: Oxidative Stress and Antioxidantsmentioning

confidence: 99%

“…While oral intake 10 days after noise exposure did not improve overall cell survival, it still preserved auditory function (Chen et al, 2020 ), suggesting a mild protective effect of HK-2 when taken several days after the exposure. Given that HK-2 is efficient at reducing noise-induced cell damage, it could be administered orally and it shows no side effects, at least in rats, it has been suggested as a new treatment option for NIHL (Chen et al, 2020 ). However, further studies will be needed to confirm that HK-2 is a valid therapeutic alternative without adverse side effects on humans.…”

Section: Oxidative Stress and Antioxidantsmentioning

confidence: 99%

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Antioxidants and Vasodilators for the Treatment of Noise-Induced Hearing Loss: Are They Really Effective?

Alvarado

Fuentes–Santamaría

Juı́z

2020

Front. Cell. Neurosci.

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We live in a world continuously immersed in noise, an environmental, recreational, and occupational factor present in almost every daily human activity. Exposure to high-level noise could affect the auditory function of individuals at any age, resulting in a condition called noise-induced hearing loss (NIHL). Given that by 2018, more than 400 million people worldwide were suffering from disabling hearing loss and that about one-third involved noise over-exposure, which represents more than 100 million people, this hearing impairment represents a serious health problem. As of today, there are no therapeutic measures available to treat NIHL. Conventional preventive measures, including public awareness and education and physical barriers to noise, do not seem to suffice, as the population is still being affected by damaging noise levels. Therefore, it is necessary to develop or test pharmacological agents that may prevent and/or diminish the impact of noise on hearing. Data availability about the pathophysiological processes involved in triggering NIHL has allowed researchers to use compounds, that could act as effective therapies, by targeting specific mechanisms such as the excess generation of free radicals and blood flow restriction to the cochlea. In this review, we summarize the advantages/disadvantages of these therapeutic agents, providing a critical view of whether they could be effective in the human clinic.

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Antioxidative Stress‐Induced Destruction to Cochlear Cells Caused by Blind Antioxidant Therapy

Li,

Chen,

Lin

et al. 2024

Otolaryngol.--head neck surg.

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ObjectiveVerification that blind and excessive use of antioxidants leads to antioxidant stress which exacerbates cochlear cell damage.Study DesignBasic research.SettingThe Third Affiliated Hospital of Sun Yat‐Sen University.MethodsWe compared and quantified hair cell‐like house ear institute‐organ of corti 1 (HEI‐OC1) cell density, cell viability, and apoptosis caused by different concentrations of N‐acetylcysteine (NAC) via Hoechst staining, Cell Counting Kit 8, Hoechst with propidium iodide staining, and Annexin V with propidium iodide (PI) staining. Apoptosis induced by high concentrations of M40403 and coenzyme Q10 in cochlear explants was analyzed and compared by cochlear dissection and activated caspase 3 labeling.ResultsWith the increase of NAC concentration (0‐1000 μmol/L), cell density decreased consequently and reached the lowest at 1000 μmol/L (****P ≤ .0001). Cell viability is also declining (**P < .01). The number of Annexin V‐fluorescein isothiocyanate‐labeled cells and PI‐labeled cells increased with increasing NAC concentration after treatment of HEI‐OC1 cells for 48 hours. The proportion of apoptotic cells also rose (*P < .05, **P < .01). Cochlear hair cells (HCs) treated with low concentrations of M40403 and coenzyme Q10 for 48 hours showed no damage. When the concentrations of M40403 and coenzyme Q10 were increased (concentrations＞30 μmol/L), HC damage began, followed by a dose‐dependent increase in HC loss (*P < .001, **P < .0001). Activated caspase‐3 was clearly apparent in cochlear explants treated with 50 μmol/L M40403 and coenzyme Q10 compared with cochlear explants without added M40403 and coenzyme Q10.ConclusionThese experimental results suggest that inappropriate application of antioxidants can cause severe damage to normal cochlear HCs.

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Novel oral multifunctional antioxidant prevents noise-induced hearing loss and hair cell loss

Cited by 30 publications

References 52 publications

Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

Antioxidants and Vasodilators for the Treatment of Noise-Induced Hearing Loss: Are They Really Effective?

Antioxidative Stress‐Induced Destruction to Cochlear Cells Caused by Blind Antioxidant Therapy

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