Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Glutz, Andrea; Leitmeyer, Katharina; Setz, Cristian; Brand, Yves; Bodmer, Daniel

doi:10.1159/000438918

Cited by 11 publications

(8 citation statements)

References 44 publications

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“…The gentamicin-induced damage to HCs that we observed was similar to that observed in our earlier study [Glutz et al, 2015] and in studies by other groups [Battaglia et al, 2003;Chung et al, 2006]. In vitro aminoglycoside toxicity is a common model for investigating ototoxicity, and several recent studies using gentamicin revealed critical intracellular events that mediate HC survival [Battaglia et al, 2003;Brand et al, 2015;Caelers et al, 2010;Chung et al, 2006].…”

Section: Brimonidine Protects Ohcs From Gentamicininduced Toxicitysupporting

confidence: 88%

Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

2017

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Brimonidine, an alpha-2 adrenergic receptor (α₂-AR) agonist, has neuroprotective effects in the visual system and in spiral ganglion neurons. Auditory hair cells (HCs) express all 3 α₂-AR subtypes, but their roles in HCs remain unknown. This study investigated the effects of brimonidine on auditory HCs that were also exposed to gentamicin, which is toxic to HCs. Organ of Corti explants were exposed to gentamicin in the presence or absence of brimonidine, and the α₂-AR protein expression levels and Erk1/2 and Akt phosphorylation levels were determined. Brimonidine had a protective effect on auditory HCs against gentamicin-induced toxicity that was blocked by yohimbine. This suggested that the protective effect of brimonidine on HCs was mediated by the α₂-AR. None of the treatments altered α₂-AR protein expression levels, and brimonidine did not significantly change the activation levels of the Erk1/2 and Akt proteins. These observations indicated that brimonidine, acting directly via α₂-AR, protects HCs from gentamicin-induced toxicity. Therefore, brimonidine shows potential for preventing or treating sensorineural hearing loss.

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Section: Brimonidine Protects Ohcs From Gentamicininduced Toxicitysupporting

confidence: 88%

Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

2017

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“…After ototoxic stress, the behavior of the isolated inner ear cells of the rat pups in our study were tested and found to be comparable to the previous experiments done in our laboratory; profound hair cell damage was caused by cisplatin and less so by gentamicin ( Fig 1 ). [ 10 – 12 ] We then collected the supernatant from the control and intervention groups. The concentrations of cisplatin and gentamicin were selected according to established ototoxic concentrations from previous experiments.…”

Section: Resultsmentioning

confidence: 99%

Inner ear exosomes and their potential use as biomarkers

et al. 2018

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Exosomes are nanovesicles involved in intercellular communications. They are released by a variety of cell types; however, their presence in the inner ear has not been described in the literature. The aims of this study were to determine if exosomes are present in the inner ear and, if present, characterize the changes in their protein content in response to ototoxic stress. In this laboratory investigation, inner ear explants of 5-day-old Wistar rats were cultured and treated with either cisplatin or gentamicin. Hair cell damage was assessed by confocal microscopy. Exosomes were isolated using ExoQuick, serial centrifugation, and mini-column methods. Confirmation and characterization of exosomes was carried out using transmission electron microscopy (TEM), ZetaView, BCA protein analysis, and proteomics. Vesicles with a typical size distribution for exosomes were observed using TEM and ZetaView. Proteomic analysis detected typical exosome markers and markers for the organ of Corti. There was a statistically significant reduction in the exosome protein level and number of particles per cubic centimeter when the samples were exposed to ototoxic stress. Proteomic analysis also detected clear differences in protein expression when ototoxic medications were introduced. Significant changes in the proteomes of the exosomes were previously described in the context of hearing loss and ototoxic treatment. This is the first report describing exosomes derived from the inner ear. These findings may present an opportunity to conduct further studies with the hope of using exosomes as a biomarker to monitor inner ear function in the future.

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“…Metformin reduced neuroinflammation and hippocampal cell death in diabetic mice, with subsequent improved performance in spatial memory tests [45] and was shown to be neuroprotective in experimental Parkinson’s disease [46]. Furthermore, metformin protected CA1 pyramidal cell of the hippocampus from ischemia/reperfusion injury [47] and protected cochlear hair cells from gentamicin-induced toxicity [48]. In addition to its neuroprotective effects, metformin has recently been shown to potently promote neurogenesis in the hippocampus and cortex by enhancing neural precursor self-renewal, proliferation, and differentiation [42, 49].…”

Section: Introductionmentioning

confidence: 99%

Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis

Muri

Zemp

et al. 2019

J Neuroinflammation

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Background Pneumococcal meningitis is associated with high risk of neurological sequelae such as cognitive impairment and hearing loss. These sequelae are due to parenchymal brain and inner ear damage primarily induced by the excessive inflammatory reaction in response to bacterial brain invasion. Metformin—a biguanide drug to treat diabetes mellitus type 2—was recently found to suppress neuroinflammation and induce neuroregeneration. This study evaluated the effect of metformin adjunctive to antibiotics on neuroinflammation, brain and inner ear damage, and neurofunctional outcome in experimental pediatric pneumococcal meningitis. Methods Eleven-day-old Wistar rats were infected intracisternally with 5.22 ± 1.27 × 10 3 CFU Streptococcus pneumoniae and randomized for treatment with metformin (50 mg/kg, i.p., once daily for 3 weeks) plus ceftriaxone (100 mg/kg, i.p., bid, n = 61) or ceftriaxone monotherapy ( n = 79). Cortical damage and hippocampal apoptosis were evaluated histomorphometrically 42 h post infection. Cerebrospinal fluid cytokine levels were analyzed during acute infection. Five weeks post infection, auditory brainstem responses were measured to determine hearing thresholds. Spiral ganglion neuron density and abundance of recently proliferated and integrated hippocampal granule neurons were assessed histologically. Additionally, the anti-inflammatory effect of metformin was studied in primary rat astroglial cells in vitro. Results Upon pneumococcal infection, metformin treatment significantly reduced levels of inflammatory cytokines and nitric oxide production in cerebrospinal fluid and in astroglial cell cultures in vitro ( p < 0.05). Compared to animals receiving ceftriaxone monotherapy, adjunctive metformin significantly reduced cortical necrosis ( p < 0.02) during acute infection and improved median click-induced hearing thresholds (60 dB vs. 100 dB, p < 0.002) 5 weeks after infection. Adjuvant metformin significantly improved pure tone hearing thresholds at all assessed frequencies compared to ceftriaxone monotherapy ( p < 0.05) and protected from PM-induced spiral ganglion neuron loss in the inner ear ( p < 0.05). Conclusion Adjuvant metformin reduces brain injury during pneumococcal meningitis by decreasing the excessive neuroinflammatory response. Furthermore, it protects spiral ganglion neurons in the inner ear and improves hearing impairments after experimental pneumococcal meningitis. These results identify adjuvant metformin as a promising therapeutic option to improve the outcome after pediatric pneumococcal meningitis. Electronic supplementary material The online version of this article (10.1186/s12974-019-1549-6) cont...

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Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Cited by 11 publications

References 44 publications

Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin

Inner ear exosomes and their potential use as biomarkers

Metformin mediates neuroprotection and attenuates hearing loss in experimental pneumococcal meningitis

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