ACS67, a Hydrogen Sulfide–Releasing Derivative of Latanoprost Acid, Attenuates Retinal Ischemia and Oxidative Stress to RGC-5 Cells in Culture

Abstract

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.

Hydrogen Sulfide in Biochemistry and Medicine

“…The H 2 S-cysteine-GSH connection has been documented often in the biomedical literature (26,59,93,94,141,147,158). Five factors are currently considered to contribute to the H 2 Sstimulated increase in intracellular GSH levels: (i) enhancement of cellular glutamate uptake (194), (ii) a H 2 S-induced increase in the level of gamma-glutamylcysteine synthetase and cystine transporter activity in the cell (94) (iii), reduction of cystine into cysteine by H 2 S in the extracellular space, and transport of cysteine into cells by the cysteine transporter (93), (iv) H 2 S stimulation of nuclear transcription factor Nrf2, which in turn upregulates GSH synthesis and transport (9,26), and (v) a decrease in the activity of GSH-catabolizing enzymes (184).…”

“…The slow-releasing H 2 S prodrug ACS67 (a latanoprostdithiolethione conjugate) was shown to attenuate retinal ischemic damage following experimental elevation of retinal pressure in rats, with ACS67 being more potent than latanoprost (147). The same authors found that ACS67 significantly attenuated hydrogen peroxide-induced damage to transformed neural precursor cells known to exhibit a number of characteristics associated with retinal ganglion cells (RGC).…”

Effect of Hydrogen Sulfide Donors on Intraocular Pressure in Rabbits

“…For instance, H 2 S can alter neurotransmitter release from tissues of the anterior uvea and retina and can exert a neuroprotective action in the retina. 10,[15][16][17]19,27,28 There is evidence that H 2 S can relax both isolated mammalian irides and posterior ciliary arteries.…”

Degeneration and Dysfunction of Retinal Neurons in Acute Ocular Hypertensive Rats: Involvement of Calpains

“…As performed in previous studies, 20 our ERG results for experimental groups were expressed as percent of these control values. Seven days after OH, amplitudes of the a-and b-waves and OPs were significantly decreased to 74, 29, and 27%, respectively (Fig.…”