Long-acting genipin derivative protects retinal ganglion cells from oxidative stress models in vitro and in vivo through the Nrf2/antioxidant response element signaling pathway.

Abstract

Previously, we reported that genipin, a herbal iridoid, had neuritogenic and neuroprotective actions on PC12 cells. Although nitric oxide (NO)-activated signalings were proposed to be neuritogenic, the neuroprotective action of genipin remains to be elucidated. From the standpoint of NO activation, we tested a possible protective mechanism through the nitrosative Kelch-like ECH-associated protein (Keap1)/NF-E2-related factor 2 (Nrf2)-antioxidant response element pathway in rat retinal ganglion cells (RGC-5 cells) in culture, and in vivo, against hydrogen peroxide and optic nerve injury (ONI), respectively, using a long-acting (1R)-isoPropyloxygenipin (IPRG001). IPRG001 induced NO generation and the expressions of antioxidative enzymes, such as heme oxygenase-1 (HO-1), in RGC-5 cells. The protective action of IPRG001 depended on HO-1 and NO induction. We found that S-nitrosylation of Keap1 by IPRG001 may contribute to translocation of Nrf2 to the nucleus and triggered transcriptional activation of antioxidative enzymes. Furthermore, apoptotic cells were increased and 4-hydroxy-2-nonenal was accumulated in rat retina following ONI. Pre-treatment with IPRG001 almost completely suppressed apoptosis and accumulation of 4-hydroxy-2-nonenal in RGCs following ONI accompanied by HO-1 induction. These data demonstrate for the first time that IPRG001 exerts neuroprotective action in RGCs in vitro and in vivo, through the Nrf2/antioxidant response element pathway by S-nitrosylation against oxidative stress.

• Authors: Yoshiki Koriyama, Kenzo Chiba, Matsumi Yamazaki, Hirokazu Suzuki, Ken-ichiro Muramoto, Satoru Kato
• Journal: Journal of neurochemistry (J Neurochem) Vol. 115 Issue 1 Pg. 79-91 (Oct 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20681953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.

Chemical References

• Aldehydes
• Antioxidants
• Chromatin
• Coloring Agents
• Cysteine Proteinase Inhibitors
• Intracellular Signaling Peptides and Proteins
• Iridoid Glycosides
• Iridoids
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• RNA, Small Interfering
• Tetrazolium Salts
• Thiazoles
• Nitric Oxide
• RNA
• genipin
• Heme Oxygenase-1
• thiazolyl blue
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Blotting, Western
• Cell Death (drug effects)
• Cell Line
• Chromatin (metabolism)
• Coloring Agents
• Cysteine Proteinase Inhibitors (pharmacology)
• Heme Oxygenase-1 (genetics)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• In Situ Nick-End Labeling
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Iridoid Glycosides
• Iridoids (pharmacology)
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2 (metabolism)
• Nitric Oxide (biosynthesis)
• Oxidative Stress (drug effects)
• RNA (biosynthesis, genetics)
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Response Elements (physiology)
• Retinal Ganglion Cells (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tetrazolium Salts
• Thiazoles