Sphingosine 1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death: implications for otoprotective therapy.

Deron R. Herr,Rich Rivera,Jerold Chun,Yee Xin Peh,Chang-Wook Lee,Marie J. Y. Reolo,Wei Wang,Ian C. Paterson

doi:10.1038/srep24541

Abstract

Ototoxic drugs, such as platinum-based chemotherapeutics, often lead to permanent hearing loss through apoptosis of neuroepithelial hair cells and afferent neurons of the cochlea. There is no approved therapy for preventing or reversing this process. Our previous studies identified a G protein-coupled receptor (GPCR), S1P2, as a potential mediator of otoprotection. We therefore sought to identify a pharmacological approach to prevent cochlear degeneration via activation of S1P2. The cochleae of S1pr2−/− knockout mice were evaluated for accumulation of reactive oxygen species (ROS) with a nitro blue tetrazolium (NBT) assay. This showed that loss of S1P2 results in accumulation of ROS that precedes progressive cochlear degeneration as previously reported. These findings were supported by in vitro cell-based assays to evaluate cell viability, induction of apoptosis, and accumulation of ROS following activation of S1P2 in the presence of cisplatin. We show for the first time, that activation of S1P2 with a selective receptor agonist increases cell viability and reduces cisplatin-mediated cell death by reducing ROS. Cumulatively, these results suggest that S1P2 may serve as a therapeutic target for attenuating cisplatin-mediated ototoxicity.

Highlights

Hair cells of the cochlea are specialized neuroepithelial cells required for the transduction of vibrational force into the perception of hearing
Previous work by our group and others provide evidence that S1P2, a G protein-coupled receptor (GPCR) that mediates the effects of sphingosine 1-phosphate (S1P), may represent such a target
While there is strong evidence that this mechanism contributes to loss of cochlear integrity, we note that S1P2 is expressed in the hair cells and supporting cells of the cochlea, with expression increasing over time, coincident with the progression of the cochlear degeneration[19]

Summary

Introduction

Hair cells of the cochlea are specialized neuroepithelial cells required for the transduction of vibrational force into the perception of hearing. S1P is a bioactive lipid signalling molecule that is known to act as a potent extracellular ligand for a family of five cognate GPCRs, S1P1–S1P54 These receptors have distinct but overlapping patterns of expression, and are known to be important activators of many cellular processes, such as cell proliferation, cell death, cytoskeletal rearrangement, migration/motility, and differentiation[5,6]. Many of the biomedically relevant roles of S1P receptors have been elucidated with the study of genetically engineered knockout mice These studies have shown that S1P signalling is essential for a number of processes including vascular maturation[11], lymphocyte trafficking[12], epithelial sheet migration[13], B cell regulation[14], egress of natural killer cells[15], and mechanisms underlying the multiple sclerosis drug known as fingolimod (Gilenya)[16,17,18]. We demonstrate that activation of S1P2 is associated with reduction of ROS accumulation by a specific S1P2 agonist and provide proof-of-concept for its use as an otoprotective agent

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Results

Conclusion