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Elia J Duh, Marcus Karlstetter, Zhenhua Xu, Junsong Gong, Hongkwan Cho, Jing Yang, Hartmut Schirok, Linn Schneider, Mario Lobell, Martina Schaefer, Carsten Terjung, Khaled Nassar; Evaluation of a new pharmacologic strategy for Nrf2 activation for retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3203.
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The mechanistic involvement of oxidative stress and activation of retinal inflammation have been described for the pathogenesis of various retinal diseases. Nrf2 is a master regulatory factor with cytoprotective antioxidant and anti-inflammatory properties. Pharmacologic activation of Nrf2 has thus far focused on drugs that covalently modify the Nrf2 inhibitor Keap1. In this study, we investigated the therapeutic potential of a drug (18e) that activates the Nrf2 pathway through Keap1-Nrf2 protein-protein interaction (PPI) inhibition.
To determine transcription profiles for anti-oxidant as well as pro-inflammatory marker genes, human retinal endothelial cells (HREC) and LPS-activated RAW264 macrophages were treated with 18e (Keap1-Nrf2 PPI inhibitor) for 6 and 24 hours followed by qRT-PCR analysis.Plasma concentration of 18e was analyzed in male Wister rats following a single subcutaneous injection (s.c) of 10 mg/kg or 1 mg/kg intravenous (i.v) bolus injection. Using systemic administration of 18e, retinal target engagement was evaluated by assessing expression of Nrf2 target genes by qRT-PCR analyses. Finally, in vivo therapeutic efficacy of 18e was tested in the retinal ischemia reperfusion model (IR) and analyzed by optokinetic tracking (OKT).
18e treatment caused a significant induction of antioxidant genes in HREC and suppression of pro-inflammatory genes in RAW264 macrophages. After i.v. administration, 18e exhibited a high clearance and short half-life. In contrast, bioavailability of 18e was greater after 10 mg/kg s.c. application. Treatment with 18e caused a significant up-regulation of antioxidant genes (rTXNRD, p value < 0.05) in rat I/R retinas. I/R animals treated with 18e maintained better visual acuity in terms of spatial frequency in optomotry test (p value< 0.001).
Nrf2-activation by the direct Nrf2/Keap1 PPI inhibitor 18e induced anti-oxidant response and reduced pro-inflammatory gene expression in vitro and in vivo. This was associated with improvement of visual function in IR rats. Targeting the ocular Nrf2/Keap1 pathway via systemic approach is feasible and could be a new pharmacologic strategy for Nrf2 activation for the treatment of ocular diseases driven by oxidative stress and pro-inflammatory processes.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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