Ceramide/sphingomyelin cycle involvement in gentamicin-induced cochlear hair cell death

Ceramide, a sphingolipid metabolite, regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular differentiation. Exogenously administered ceramide reportedly increased cochlear hair cell death due to gentamicin-induced ototoxicity. Ceramide is mainly generated via a ceramide/sphingomyelin cycle by sphingomyelinase and sphingomyelin synthase or via de novo synthesis by serine palmitoyltransferase and ceramide synthase. This study was designed to investigate the possible involvement of neutral sphingomyelinase, sphingomyelin synthase, or serine palmitoyltransferase in hair cell death due to gentamicin. The basal turns of the organ of Corti of Sprague-Dawley rats were dissected on postnatal days 3-5. Cochlear cultures were exposed to media containing 35 μM gentamicin for 48 h to assess the effects of GW4869 (a neutral sphingomyelinase inhibitor), 2-hydroxyoleic acid (a sphingomyelin synthase activator), and myriocin (a serine palmitoyltransferase inhibitor). Hair cell loss was significantly decreased in the presence of GW4869 or 2-hydroxyoleic acid. Myriocin had no significant effects against gentamicin-induced hair cell loss. In addition, neutral sphingomyelinase was activated by gentamicin exposure. The present findings strongly suggest that the ceramide/sphingomyelin cycle plays an important role in the protection of hair cells against gentamicin-induced ototoxicity.