Metformin Protects Against Noise-Induced Hearing Loss in Male Mice

Catherine L. Kennedy, Benjamin Shuster, Reza Amanipour, Beatrice Milon, Priya Patel, Ran Elkon, Ronna Hertzano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Hypothesis Metformin treatment will protect mice from noise-induced hearing loss (NIHL). Background We recently identified metformin as the top-ranking, Food and Drug Administration-approved drug to counter inner ear molecular changes induced by permanent threshold shift-inducing noise. This study is designed to functionally test metformin as a potential otoprotective drug against NIHL. Methods Male and female B6CBAF1/J mice were obtained at 7 to 8 weeks of age. A cohort of the females underwent ovariectomy to simulate menopause and eliminate the effect of ovarian-derived estrogens. At 10 weeks of age, mice underwent a permanent threshold shift-inducing noise exposure (102.5 or 105 dB SPL, 8-16 kHz, 2 h). Auditory brainstem response (ABR) thresholds were obtained at baseline, 24 h after noise exposure, and 1 week after noise exposure. Mice were administered metformin (200 mg/kg/d) or a saline control in their drinking water after the baseline ABR and for the remainder of the study. After the 1-week ABR, mice were euthanized and cochlear tissue was analyzed. Results Metformin treatment reduced the 1-week ABR threshold shift at 16 kHz (p < 0.01; d = 1.20) and 24 kHz (p < 0.01; d = 1.15) as well as outer hair cell loss in the 32-45.5 kHz range (p < 0.0001; d = 2.37) in male mice. In contrast, metformin treatment did not prevent hearing loss or outer hair cell loss in the intact or ovariectomized female mice. Conclusions Metformin exhibits sex-dependent efficacy as a therapeutic for NIHL. These data compel continued investigation into metformin's protective effects and demonstrate the importance of evaluating the therapeutic efficacy of drugs in subjects of both sexes.

Original languageEnglish
Pages (from-to)956-963
Number of pages8
JournalOtology and Neurotology
Volume44
Issue number9
DOIs
StatePublished - 1 Oct 2023

Funding

FundersFunder number
University of Maryland School of Medicine Center for Innovative Biomedical Resources Core Confocal LaboratoryS10 OD026698
National Institutes of HealthR01DC013817
U.S. Department of DefenseW81XWH2110578, MR130240
National Institute on Deafness and Other Communication DisordersDC000094-01
United States-Israel Binational Science Foundation2021294

    Keywords

    • Metformin
    • Mouse model
    • Noise-induced hearing loss
    • Otoprotection
    • Sex differences
    • Therapeutic

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