Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo

NEUROSCIENCE LETTERS

卷:583

Article

Oishi, Naoki^1,2  Kendall, Ann²  Schacht, Jochen² 

[1] Keio Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Tokyo 1608582, Japan

[2] Univ Michigan, Dept Otolaryngol, Kresge Hearing Res Inst, Ann Arbor, MI 48109 USA

关键词: Metformin;    Gentamicin;    Cochlear explants;    Guinea pigs;    Outer hair cells;    Ototoxicity;   

DOI  :  10.1016/j.neulet.2014.09.028

来源: Elsevier

【 摘 要 】

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 130 mg/kg body weight for 14 days induced significant threshold shifts as determined by auditory brain stem responses. Metformin (30, 75, or 100 mg/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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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