Possible role of HMG-CoA reductase inhibitors for the treatment of sudden sensorineural hearing loss (SSHL)

Borghi, Claudio; Modugno, G.C.; Pirodda, Antonio

doi:10.1054/mehy.2001.1535

Cited by 14 publications

(21 citation statements)

References 13 publications

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“…Work done in the retina has shown that simvastatin increases Akt phosphorylation in vivo , indicating that the PI3K/Akt pathway contributes to the central nervous system protective effects achieved [26]. In a previous study, we demonstrated that PI3K mediates HC survival and opposes gentamicin toxicity in neonatal rat OC [9].…”

Section: Discussionmentioning

confidence: 90%

“…It has been hypothesized that statins might be useful as a treatment for sudden sensorineural hearing loss due to their metabolic and hemodynamic effects [26]. Syka et al demonstrated that atrovastin had a positive effect on the deterioration of inner ear function with age in mice by analysing distortion product otoacoustic emissions (DPOAE).…”

Section: Discussionmentioning

confidence: 99%

“…They suggested that atrovastin reduces endothelial inflammatory effects that influence the blood supply to the inner ear [25]. While no experiments were performed, Borghi et al hypothesized that statins might be useful as a treatment for sensorineural hearing loss due to their metabolic and hemodynamic effects [26]. However, a prospective, randomized, double-blinded clinical trial by Olzowy et al did not show an effect of atrovastin on progression of sensorineural hearing loss in the elderly [27].…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro

et al. 2011

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BackgroundInhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, are commonly used as cholesterol-lowering drugs. During the past decade, evidence has emerged that statins also have neuroprotective effects. Research in the retina has shown that simvastatin, a commonly used statin, increases Akt phosphorylation in vivo, indicating that the PI3K/Akt pathway contributes to the protective effects achieved. While research about neuroprotective effects have been conducted in several systems, the effects of statins on the inner ear are largely unknown.ResultsWe evaluated whether the 3-hydroxy-3-methylglutaryl-coenzyme A reductase is present within the rat cochlea and whether simvastatin is able to protect auditory hair cells from gentamicin-induced apoptotic cell death in a in vitro mouse model. Furthermore, we evaluated whether simvastatin increases Akt phosphorylation in the organ of Corti. We detected 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in organ of Corti, spiral ganglion, and stria vascularis by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, we observed a dose-dependent and significant reduction of hair cell loss in organs of Corti treated with simvastatin in addition to gentamicin, as compared to samples treated with gentamicin alone. The protective effect of simvastatin was reversed by addition of mevalonate, a downstream metabolite blocked by simvastatin, demonstrating the specificity of protection. Finally, Western blotting showed an increase in organ of Corti Akt phosphorylation after simvastatin treatment in vitro.ConclusionThese results suggest a neuroprotective effect of statins in the inner ear, mediated by reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase metabolism and Akt activation.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro

et al. 2011

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“…Some reports have proposed that antilipidemic drugs may have a role in the treatment of ISSNHL. Borghi et al . reported that HMG‐CoA reductase inhibitors may have a role in the treatment of ISSNHL with potential benefits at the cochlear level.…”

Section: Discussionmentioning

confidence: 99%

The correlation between lipoprotein ratios and hearing outcome in idiopathic sudden sensorineural hearing loss patients

Lin

Wang

Chou

et al. 2015

Clinical Otolaryngology

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“…The statin family of drugs, HMG CoA-reductase inhibitors, was once hypothesized to be useful as a treatment for sensorineural hearing loss through their metabolic and hemodynamic effects (Borghi et al 2002). Studies with atorvastatin-treated mice have shown decreased expression of intercellular and vascular adhesion molecules in the aortic wall, suggesting that reducing endothelial inflammatory effects may contribute to improved hair cell function by influencing the blood supply to the inner ear (Syka et al 2007).…”

Section: Some Drugs May Have Both Protective and Toxic Effectsmentioning

confidence: 99%

Using the Zebrafish Lateral Line to Screen for Ototoxicity

Chiu

Cunningham

Raible

et al. 2008

JARO

183

134

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The zebrafish is a valuable model for studying hair cell development, structure, genetics, and behavior. Zebrafish and other aquatic vertebrates have hair cells on their body surface organized into a sensory system called the lateral line. These hair cells are highly accessible and easily visualized using fluorescent dyes. Morphological and functional similarities to mammalian hair cells of the inner ear make the zebrafish a powerful preparation for studying hair cell toxicity. The ototoxic potential of drugs has historically been uncovered by anecdotal reports that have led to more formal investigation. Currently, no standard screen for ototoxicity exists in drug development. Thus, for the vast majority of Food and Drug Association (FDA)-approved drugs, the ototoxic potential remains unknown. In this study, we used 5-day-old zebrafish larvae to screen a library of 1,040 FDA-approved drugs and bioactives (NINDS Custom Collection II) for ototoxic effects in hair cells of the lateral line. Hair cell nuclei were selectively labeled using a fluorescent vital dye. For the initial screen, fish were exposed to drugs from the library at a 100-μM concentration for 1 h in 96-well tissue culture plates. Hair cell viability was assessed in vivo using fluorescence microscopy. One thousand forty drugs were rapidly screened for ototoxic effects. Seven known ototoxic drugs included in the library, including neomycin and cisplatin, were positively identified using these methods, as proof of concept.Fourteen compounds without previously known ototoxicity were discovered to be selectively toxic to hair cells. Dose-response curves for all 21 ototoxic compounds were determined by quantifying hair cell survival as a function of drug concentration. Dose-response relationships in the mammalian inner ear for two of the compounds without known ototoxicity, pentamidine isethionate and propantheline bromide, were then examined using in vitro preparations of the adult mouse utricle. Significant dose-dependent hair cell loss in the mouse utricle was demonstrated for both compounds. This study represents an important step in validating the use of the zebrafish lateral line as a screening tool for the identification of potentially ototoxic drugs.

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Possible role of HMG-CoA reductase inhibitors for the treatment of sudden sensorineural hearing loss (SSHL)

Cited by 14 publications

References 13 publications

Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro

Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro

The correlation between lipoprotein ratios and hearing outcome in idiopathic sudden sensorineural hearing loss patients

Using the Zebrafish Lateral Line to Screen for Ototoxicity

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