Hair Cell Loss Induced by Sphingosine and a Sphingosine Kinase Inhibitor in the Rat Cochlea

Abstract

Sphingolipid metabolites including ceramide, sphingosine (Sph), and sphingosine-1-phosphate (S1P) play important roles in the regulation of cell survival and death. Sphingosine kinase (Sk) phosphorylates Sph to S1P. Sk is reportedly overexpressed in various cancer cells, and Sk inhibitors are therefore a target of anti-tumor therapy. However, the effects of Sph and Sk inhibitors on cochlear hair cells were unknown. In the present study, expression of Sk isotypes in the cochlea was examined. In addition, the changes in Sk activity induced by cisplatin (CDDP) and the effects of an Sk inhibitor, Sph, and S1P on CDDP ototoxicity were investigated using tissue culture techniques. Cochleae were dissected from Sprague–Dawley rats on postnatal days 3–5. Organ of Corti explants were exposed to 5 lM CDDP for 48 h with or without the Sk inhibitor, Sph, or S1P. Both Sk1 and Sk2 were expressed in the normal cochlea. CDDP activated Sk. The Sk inhibitor itself caused hair cell loss at a high concentration, and at lower concentrations, it increased CDDP-induced hair cell loss. Sph itself also induced hair cell death and increased hair cell loss induced by CDDP. However, S1P decreased hair cell loss induced by CDDP. Sk inhibitor has the function by increasing ototoxic Sph and decreasing otoprotective S1P and therefore potentially causes ototoxicity. Consideration of the possibility of ototoxicity is required in the usage of Sk inhibitors.