The influence of sphingosine-1-phosphate receptor antagonists on gentamicin-induced hair cell loss of the rat cochlea

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates various critical biological processes, such as cell proliferation, survival, migration, and angiogenesis. The action of S1P is exerted by its binding to 5 specific G protein-coupled S1P receptors (S1PR), S1PR1-S1PR5. Aminoglycoside antibiotics including gentamicin induce cochlear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this type of cochlear injury. S1P acts as a cochlear protectant against gentamicin ototoxicity. In the present study, expression of S1PRs in the cochlea was examined. In addition, the effects of S1PR antagonists on gentamicin ototoxicity were investigated using tissue culture techniques. Cochleas were dissected from Sprague-Dawley rats on postnatal days 3-5. Basal turn organ of Corti explants were exposed to 35 μM gentamicin for 48 h with or without S1PR antagonists. S1PR(1-3) were expressed in the organ of Corti and spiral ganglion. The S1PR2 antagonist increased gentamicin-induced hair cell loss, while the S1PR1 and S1PR3 antagonists did not affect gentamicin ototoxicity. These results indicate the possibility that S1P act as a cochlear protectant against gentamicin ototoxicity via activation of S1PR2.