A hypothesis for treating inflammation and oxidative stress with hydrogen sulfide during age-related macular degeneration

Age-related macular degeneration（AMD） is a leading cause of blindness and is becoming a global crisis since affected people will increase to 288 million by 2040.Genetics,age,diabetes,gender,obesity,hypertension,race,hyperopia,iris-color,smoking,sun-light and pyroptosis have varying roles in AMD,but oxidative stress-induced inflammation remains a significant driver of pathobiology.Eye is a unique organ as it contains a remarkable oxygengradient that generates reactive oxygen species（ROS） which upregulates inflammatory pathways.ROS becomes a source of functional and morphological impairments in retinal pigment epithelium（RPE）,endothelial cells and retinal ganglion cells.Reports demonstrated that hydrogen sulfide（H2S） acts as a signaling molecule and that it may treat ailments.Therefore,we propose a novel hypothesis that H2S may restore homeostasis in the eyes thereby reducing damage caused by oxidative injury and inflammation.Since H_2S has been shown to be a powerful antioxidant because of its free-radicals＇ inhibition properties in addition to its beneficial effects in age-relatedconditions,therefore,patients may benefit from H2S salubrious effects not only by minimizing their oxidant and inflammatory injuries to retina but also by lowering retinal glutamate excitotoxicity.

Hydrogen sulfide intervention in cystathionine-β-synthase mutant mouse helps restore ocular homeostasis

AIM: To investigate the applications of hydrogen sulfide(H2 S) in eye-specific ailments in mice.METHODS: Heterozygous cystathionine-β-synthase(CBS+/-) and wild-type C57 BL/6 J(WT) mice fed with or without high methionine diet(HMD) were administered either phosphate buffered saline(PBS) or the slow-release H2 S donor: GYY4137. Several analyses were performed to study GYY4137 effects by examining retinal lysates for key protein expressions along with plasma glutamate and glutathione estimations. Intraocular pressure(IOP) was monitored during GYY4137 treatment; barium sulfate and bovine serum albumin conjugated fluorescein isothiocyanate(BSA-FITC) angiographies were performed for examining vasculature and its permeability post-treatment. Visionguided behavior was also tested employing novel object recognition test(NORT) and light-dark box test(LDBT) recordings.RESULTS: CBS deficiency(CBS+/-) coupled with HMD led disruption of methionine/homocysteine(Hcy) metabolism leading to hyperhomocysteinemia(HHcy) in CBS+/-mice as reflected by increased Hcy, and s-adenosylhomocysteine hydrolase(SAHH) levels. Unlike CBS, cystathionine-γ lyase(CSE), methylenetetrahydrofolate reductase(MTHFR) levels which were reduced but compensated by GYY4137intervention. Heightened oxidative and endoplasmic reticulum(ER) stress responses were mitigated by GYY4137 effects along with enhanced glutathione(GSH) levels. Increased glutamate levels in CBS+/-strain were prominent than WT mice and these mice also exhibited higher IOP that was lowered by GYY4137 treatment. CBS deficiency also resulted in vision-guided behavioral impairment as revealed by NORT and LDBT findings. Interestingly, GYY4137 was able to improve CBS+/-mice behavior together with lowering their glutamate levels. Blood-retinal barrier(BRB) appeared compromised in CBS+/-with vessels' leakage that was mitigated in GYY4137 treated group. This corroborated the results for occludin(an integral plasma membrane protein of the cellular tight junctions) stabilization.CONCLUSION: Findings reveal that HHcy-induced glutamate excitotoxicity, oxidative damage, ER-stress and vascular permeability alone or together can compromise ocular health and that GYY4137 could serve as a potential therapeutic agent for treating HHcy induced ocular disorders.