In:
British Journal of Pharmacology, Wiley, Vol. 172, No. 5 ( 2015-03), p. 1237-1249
Abstract:
Nuclear factor erythroid 2‐related factor 2 ( N rf2) is a redox‐sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of the N rf2 pathway seems protective for many organs, and although a well‐known N rf2 activator, bardoxolone methyl, was evaluated clinically for treating chronic kidney disease, it was found to induce adverse events. Many bardoxolone methyl derivatives, mostly derived by chemical modifications, have already been studied. However, we adopted a biotransformation technique to obtain a novel Nrf2 activator. Experimental Approach The potent novel N rf2 activator, RS 9, was obtained from microbial transformation products. Its N rf2 activity was evaluated by determining NADPH :quinone oxidoreductase‐1 induction activity in H epa1c1c7 cells. We also investigated the effects of RS 9 on oxygen‐induced retinopathy in rats and glycated albumin‐induced blood–retinal barrier permeability in rabbits because many ocular diseases are associated with oxidative stress and inflammation. Key Results Bardoxolone methyl doubled the specific activity of Nrf2 in H epa1c1c7 cells at a much higher concentration than RS 9. Moreover, the induction of N rf2‐targeted genes was observed at a one‐tenth lower concentration of RS 9. Interestingly, the cytotoxicity of RS 9 was substantially reduced compared with bardoxolone methyl. Oral and intravitreal administration of RS 9 ameliorated the pathological scores and leakage in the models of retinopathy in rats and ocular inflammation in rabbits respectively. Conclusion and Implications N rf2 activators are applicable for treating ocular diseases and novel N rf2 activators have potential as a unique method for prevention and treatment of retinovascular disease.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2015.172.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2029728-2
SSG:
15,3
Permalink