title: Sphingosine 1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death: implications for otoprotective therapy.
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.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Department of Biology, San Diego State University, San Diego, CA, USA.
authors.forename: Deron R
authors.initials: DR
authors.lastname: Herr
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Marie J Y
authors.initials: MJ
authors.lastname: Reolo
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Yee Xin
authors.initials: YX
authors.lastname: Peh
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Chang-Wook
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Rich
authors.initials: R
authors.lastname: Rivera
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid