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Rosiglitazone acts as a neuroprotectant in retinal cells via up‐regulation of sestrin‐1 and SOD‐2
Author(s) -
Doonan Francesca,
Wallace Deborah M.,
O’Driscoll Carolyn,
Cotter Thomas G.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.05995.x
Subject(s) - rosiglitazone , thiazolidinedione , transcription factor , peroxisome proliferator activated receptor , chromatin immunoprecipitation , superoxide dismutase , microbiology and biotechnology , receptor , biology , oxidative stress , retinal , nuclear receptor , chemistry , endocrinology , gene expression , biochemistry , promoter , gene , diabetes mellitus , type 2 diabetes
Rosiglitazone is a member of the thiazolidinedione family of synthetic peroxisome proliferator‐activated receptor (PPAR) agonists. It is a selective ligand of the PPARγ subtype and functions by regulating the transcription of insulin‐responsive genes. A screen of FDA‐approved compounds identified rosiglitazone as a novel anti‐apoptotic agent in retinal cells both in vitro and in vivo , functioning as a neuroprotectant in response to oxidative and calcium stress. We have found that the likely mechanism of action is via increased protein expression of the antioxidant enzymes superoxide dismutase 2 (SOD‐2) and sestrin‐1, boosting antioxidant defences. Transcription of both genes appears to be mediated by PPARγ as their up‐regulation is reversed by the PPARγ antagonist GW9662 and proliferator hormone response elements were found in the putative promoter regions of mouse SOD‐2 and sestrin‐1. However, further investigation revealed that p53 expression was also induced in response to rosiglitazone and chromatin immunoprecipitation assays confirm that it is a bona fide target of PPARγ. Furthermore, inhibition of p53 partially blocks the observed increase in SOD‐2 and sestrin‐1 expression indicating that p53 expression is upstream of both antioxidants. We conclude that rosiglitazone may increase cell survival in retinal diseases and potentially other neuronal diseases in which oxidative stress is a key factor.