Atorvastatin slows down the deterioration of inner ear function with age in mice

Syka, Josef; Ouda, Ladislav; Nachtigal, Petr; Solichová, Dagmar; Semecký, Vladimír

doi:10.1016/j.neulet.2006.10.032

Cited by 47 publications

(61 citation statements)

References 32 publications

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“…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). Treated mice showed decreased expression of intracellular and vascular adhesion molecules in the aortic wall and the authors suggest that reduced endothelial inflammatory effects may contribute to better OHC survival by influencing blood supply to the inner ear [25]. While Syka et al attribute the positive effect of statins on inner ear function on hemodynamic effects, other reports suggest that statins act through their metabolic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Syka et al demonstrated that atrovastin slows down the deterioration of inner ear function with age in mice. 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].…”

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: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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). A similar paradox was found for estrogens, which have been suggested by many to have favorable vascular effects that are protective of hearing (Kilicdag et al 2004;Hultcrantz et al 2006); estradiol valerate was identified in our study as being ototoxic to hair cells of the zebrafish lateral line.…”

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

178

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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“…Animals fed a long-term HFD show increased oxidative stress and dysfunctional mitochondria in many organs (Kartha et al, 2008;Bruce et al, 2009;Yokota et al, 2009;Ballal et al, 2010). Although some studies have shown that a higher fat intake was significantly associated with a reduced auditory function (Evans et al, 2006;Vasilyeva et al, 2009;Gopinath et al, 2011;Spankovich et al, 2011) and treatment with statins and consumption of monounsaturated fats may have a beneficial influence (Syka et al, 2007;Gopinath et al, 2011), the mechanisms of auditory dysfunction and the relationship between HFD and aging in the inner ear still remain obscure.…”

Section: Introductionmentioning

confidence: 99%

A long-term high-fat diet increases oxidative stress, mitochondrial damage and apoptosis in the inner ear of d-galactose-induced aging rats

Yang

et al. 2012

Hearing Research

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Atorvastatin slows down the deterioration of inner ear function with age in mice

Cited by 47 publications

References 32 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

Using the Zebrafish Lateral Line to Screen for Ototoxicity

A long-term high-fat diet increases oxidative stress, mitochondrial damage and apoptosis in the inner ear of d-galactose-induced aging rats

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