ACS67, a hydrogen sulfide-releasing derivative of latanoprost acid, attenuates retinal ischemia and oxidative stress to RGC-5 cells in culture.
Purpose. To determine the neuroprotective properties of a latanoprost acid derivative (ACS67) that donates the gas hydrogen sulfide (H(2)S). Methods. Ischemia to the rat retina was induced by elevation of intraocular pressure. Electroretinograms (ERGs) were recorded and the retinas analyzed 2 days later by immunohistochemistry, Western blot analysis, and RT-PCR. Hydrogen peroxide (H(2)O(2)) was used to impose an insult on RGC-5 cells in culture. The nature of the insult to cultures was quantified by the resazurin-reduction assay procedure, staining for reactive oxygen species (ROS) and for apoptosis. ACS67, its sulfurated moiety (ACS1), and latanoprost were tested for both their toxicity and ability to blunt the negative effect of H(2)O(2) on RGC-5 cells. In addition, an assay was used to see whether any of the substances influenced glutathione (GSH) levels in RGC-5 cells. Results. Partial damage to the retina in situ after ischemia was characterized by an alteration of the ERG, a reduction in the retinal localization of specific antigens and a reduction and elevation of defined retinal proteins and mRNAs. Optic nerve axonal proteins were also drastically reduced by ischemia. Most of these changes were significantly blunted by an intravitreal injection of ACS67 directly after ischemia. ACS67, ACS1, and the antioxidant epigallocatechin gallate (EGCG) all stimulated GSH levels and significantly attenuated H(2)O(2)-induced toxicity to RGC-5 cells, whereas latanoprost did not. Conclusions. ACS67 acts as an H(2)S donor through its donating moiety ACS1 and as a consequence is able to act as a neuroprotectant.
Osborne
Neville N
NN
Nuffield Laboratory of Ophthalmology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. neville.osborne@eye.ox.ac.uk
Ji
Dan
D
Abdul Majid
Aman S
AS
Fawcett
Rebecca J
RJ
Sparatore
Anna
A
Del Soldato
Piero
P
D000818:Animals; D015153:Blotting, Western; D020169:Caspases / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000633:toxicity; D006862:Hydrogen Sulfide / Q000378:metabolism*; D000077338:Latanoprost; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011461:Prostaglandins F, Synthetic / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000378:metabolism
C546828:ACS67 compound; D005904:Glial Fibrillary Acidic Protein; D011461:Prostaglandins F, Synthetic; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D000077338:Latanoprost; D008063:Thioctic Acid; D006861:Hydrogen Peroxide; D052248:Nitric Oxide Synthase Type I; D020169:Caspases; D005978:Glutathione; D006862:Hydrogen Sulfide