Protective Effects of a Lutein Ester Prodrug, Lutein Diglutaric Acid, against H2O2-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells

Chawanphat Muangnoi, Rianthong Phumsuay, Nattapong Jongjitphisut, Pasin Waikasikorn, Monsin Sangsawat, Paitoon Rashatasakhon, Luminita Paraoan, Pornchai Rojsitthisak

Research output: Contribution to journalArticle (journal)peer-review

23 Citations (Scopus)


Oxidative stress-induced cell damage and death of the retinal pigmented epithelium (RPE), a polarized monolayer that maintains retinal health and homeostasis, lead to the development of age-related macular degeneration (AMD). Several studies show that the naturally occurring antioxidant Lutein (Lut) can protect RPE cells from oxidative stress. However, the poor solubility and low oral bioavailability limit the potential of Lut as a therapeutic agent. In this study, lutein diglutaric acid (Lut-DG), a prodrug of Lut, was synthesized and its ability to protect human ARPE-19 cells from oxidative stress was tested compared to Lut. Both Lut and Lut-DG significantly decreased H2O2-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Moreover, the immunoblotting analysis indicated that both drugs exerted their protective effects by modulating phosphorylated MAPKs (p38, ERK1/2 and SAPK/JNK) and downstream molecules Bax, Bcl-2 and Cytochrome c. In addition, the enzymatic antioxidants glutathione peroxidase (GPx) and catalase (CAT) and non-enzymatic antioxidant glutathione (GSH) were enhanced in cells treated with Lut and Lut-DG. In all cases, Lut-DG was more effective than its parent drug against oxidative stress-induced damage to RPE cells. These findings highlight Lut-DG as a more potent compound than Lut with the protective effects against oxidative stress in RPE cells through the modulation of key MAPKs, apoptotic and antioxidant molecular pathways.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number9
Publication statusPublished - 29 Apr 2021


  • Antioxidants/pharmacology
  • Apoptosis Regulatory Proteins/biosynthesis
  • Catalase/biosynthesis
  • Cell Line
  • Cytochromes c/biosynthesis
  • Drug Evaluation, Preclinical
  • Epithelial Cells/drug effects
  • Gene Expression Regulation/drug effects
  • Glutathione/biosynthesis
  • Glutathione Peroxidase/biosynthesis
  • Humans
  • Hydrogen Peroxide/toxicity
  • Lutein/analogs & derivatives
  • MAP Kinase Signaling System/drug effects
  • Macular Degeneration/drug therapy
  • Molecular Structure
  • Oxidative Stress/drug effects
  • Prodrugs/pharmacology
  • Reactive Oxygen Species/metabolism
  • Retinal Pigment Epithelium/cytology


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