Sphingosine 1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death:
Deron R Herr1,2, Marie J Y Reolo1, Yee Xin Peh1
1Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
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.
Insights
Activating the S1P2 receptor may protect against hearing loss caused by chemotherapy drugs. This research shows S1P2 activation reduces cell death and reactive oxygen species, offering a potential therapeutic target for ototoxicity.
Area of Science:
- Oto-neuroscience
- Pharmacology
- Cellular Biology
Background:
- Ototoxic drugs, like platinum-based chemotherapeutics, cause permanent hearing loss by damaging cochlear cells.
- Currently, no effective therapies exist to prevent or reverse this drug-induced hearing damage.
- Previous research identified the G protein-coupled receptor (GPCR), S1P2, as a potential factor in otoprotection.
Purpose of the Study:
- To investigate if activating S1P2 can prevent cochlear degeneration.
- To explore a pharmacological strategy for otoprotection using S1P2 agonists.
Main Methods:
- Evaluated cochlear degeneration and reactive oxygen species (ROS) accumulation in S1P2 knockout mice.
- Utilized in vitro cell-based assays to assess cell viability and apoptosis.
- Examined the effects of S1P2 activation on cisplatin-induced ototoxicity in cell cultures.
Main Results:
- Loss of S1P2 in mice correlated with increased ROS and subsequent cochlear degeneration.
- Activation of S1P2 in cell cultures significantly increased cell viability.
- S1P2 activation reduced cisplatin-induced cell death by decreasing ROS levels.
Conclusions:
- S1P2 activation demonstrates otoprotective effects against cisplatin-induced damage.
- Reducing ROS accumulation via S1P2 activation is a key mechanism of protection.
- S1P2 represents a promising therapeutic target for preventing chemotherapy-induced ototoxicity.
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