Abstract | Purpose: Methods: A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. Results: H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3β phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-κB (NFκB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. Conclusions:
Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFκB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.
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Authors | Krisztina Kovacs, Alexandra Vaczy, Katalin Fekete, Petra Kovari, Tamas Atlasz, Dora Reglodi, Robert Gabriel, Ferenc Gallyas, Balazs Sumegi |
Journal | Investigative ophthalmology & visual science
(Invest Ophthalmol Vis Sci)
Vol. 60
Issue 5
Pg. 1478-1490
(04 01 2019)
ISSN: 1552-5783 [Electronic] United States |
PMID | 30973576
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytokines
- Hif1a protein, rat
- Hypoxia-Inducible Factor 1, alpha Subunit
- Intercellular Signaling Peptides and Proteins
- NF-E2-Related Factor 2
- NF-kappa B
- Nfe2l2 protein, rat
- Phthalazines
- Piperazines
- Poly(ADP-ribose) Polymerase Inhibitors
- Reactive Oxygen Species
- Parp1 protein, rat
- Poly (ADP-Ribose) Polymerase-1
- p38 Mitogen-Activated Protein Kinases
- Oxygen
- olaparib
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Topics |
- Animals
- Chronic Disease
- Cytokines
(metabolism)
- Disease Models, Animal
- Fluorescent Antibody Technique, Indirect
- Hypoxia
(complications)
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Immunoblotting
- Intercellular Signaling Peptides and Proteins
(metabolism)
- Male
- NF-E2-Related Factor 2
(metabolism)
- NF-kappa B
(metabolism)
- Oxidative Stress
- Oxygen
(toxicity)
- Phosphorylation
- Phthalazines
(therapeutic use)
- Piperazines
(therapeutic use)
- Poly (ADP-Ribose) Polymerase-1
(antagonists & inhibitors)
- Poly(ADP-ribose) Polymerase Inhibitors
(therapeutic use)
- Rats
- Rats, Wistar
- Reactive Oxygen Species
(metabolism)
- Reperfusion Injury
(metabolism, prevention & control)
- Retinal Diseases
(metabolism, prevention & control)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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