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.