title: Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo.
abstract: Metformin (N,N-dimethylbiguanidine) is a widely employed oral hypoglycemic agent for the management of type 2 diabetes mellitus. Its antioxidant properties and safe clinical use raise the possibility of preventing gentamicin-induced hearing loss in patients. Therefore, we screened the usefulness of metformin against gentamicin toxicity in murine cochlear explants and in the guinea pig in vivo. We confirmed in organ culture that metformin blocks the gentamicin-induced translocation of endonuclease G into the nucleus of outer hair cells and attenuates hair cell loss. In vivo, gentamicin treatment with 80, 100, or 130mg/kg body weight for 14 days induced significant threshold shifts as determined by auditory brain stem responses. Metformin (30, 75, or 100mg/kg for 14 days) was well tolerated without any indication of auditory side effects. However, co-administration of metformin with gentamicin in various permutations did not prevent loss of auditory function. On the contrary, combined treatment at higher dosages aggravated the gentamicin-induced threshold shifts and caused additional adverse reactions including body weight loss and premature deaths in some animals. These results caution against the use of metformin co-treatment with aminoglycosides and confirm the need for in vivo studies in order to evaluate potentially protective agents selected by in vitro screens.
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan; Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, MI 48109-5616, USA. Electronic address: oishi_naoki@z5.keio.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oishi
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, MI 48109-5616, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Kendall
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, MI 48109-5616, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D005260:Female; D005839:Gentamicins / Q000633:toxicity*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000633:toxicity; D008808:Mice, Inbred CBA
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Cochlear explants; Gentamicin; Guinea pigs; Metformin; Ototoxicity; Outer hair cells