2-Acetyl-5-tetrahydroxybutyl imidazole (THI) protects 661W cells against oxidative stress

  • Carlotta Fabiani
  • Aida Zulueta
  • Fabiola Bonezzi
  • Josefina Casas
  • Riccardo Ghidoni
  • Paola Signorelli
  • Anna Caretti
Original Article
  • 260 Downloads

Abstract

Retinal degeneration and in particular retinitis pigmentosa (RP) is associated to ceramide (Cer) accumulation and cell death induction. Cer and sphingosine-1-phosphate (S1P) belong to the sphingolipids class and exert a pro-apoptotic and pro-survival activity, respectively. Our aim is to target sphingolipid metabolism by inhibiting S1P lyase that regulates one of the S1P degradation pathways, to reduce retinal photoreceptor damage. The murine 661W cone-like cell line was pretreated with THI, an inhibitor of S1P lyase and exposed to H2O2-induced oxidative stress. 661W cell viability and apoptosis were evaluated by Trypan Blue and TUNEL assay, respectively. Protein expression of mediators of the survival/death pathway (ERK1/2, Akt, Bcl-2, Bax) was analyzed by Western blotting. RT-PCR was performed to establish HO-1 transcript changes and LC-MS analysis to measure Cer intracellular content. THI rescues inhibitory H2O2-effect on 661W cell viability and impairs H2O2-induced apoptosis by increasing Bcl-2/Bax ratio. THI administration counteracts the oxidative stress effects of H2O2 on 661W cells by activating the Nrf2/HO-1 pathway, regulating ERK and Akt phosphorylation levels, and decreasing Cer intracellular content. We conclude that sphingolipid metabolism manipulation can be considered a therapeutic target to promote photoreceptor survival.

Keywords

Sphingolipids Oxidative stress Photoreceptor Apoptosis 

Supplementary material

210_2017_1374_MOESM1_ESM.pdf (379 kb)
Supplemental file 1(PDF 378 kb)

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Health Sciences, University of MilanSan Paolo HospitalMilanItaly
  2. 2.Research Unit on Bioactive Molecules, Department of Biomedicinal ChemistryCatalan Institute of Advanced Chemistry (IQAC/CSIC)BarcelonaSpain

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