Hydrogen Sulfide in Glaucoma: Delivery System, Hypotensive and Neuroprotective Effects

Glaucoma, the leading cause of irreversible blindness worldwide, is an optic neuropathy disorder characterized by progressive degeneration of retinal ganglion cells (RGCs). More than 80 million people, including 3 million Americans, have glaucoma. Increased intraocular pressure (IOP) is a distinct marker of glaucoma. IOP in glaucoma increases from the healthy range of 10-21 mmHg to the glaucomatous level of 22-40 mmHg. Currently available drugs for glaucoma act by lowering the IOP. However, patients undergoing glaucoma therapy often experience partial blindness due to the inability of glaucoma drugs to protect the RGCs from degeneration in human subjects. An ideal glaucoma drug should not only restore healthy IOP but also offer neuroprotection and regeneration of RGCs. Hydrogen sulfide (H2S), an endogenous gasotransmitter, is found to have potential therapeutic applications in glaucoma. H2S acts as a smooth muscle relaxant, decreases trabecular meshwork volume, and decreases the IOP. It also scavenges reactive oxygen species, upregulates glutathione, and controls sympathetic neurotransmission to offer neuroprotection. Although H2S has potential as a treatment strategy for glaucoma, its application is limited by its physiochemical properties, toxicity, and ocular barriers. Hence in this study, we developed a polymeric microparticle-based drug delivery system using a model H2S donor sodium sulfide (Na2S.9H2O). A quality-by-design (QbD) approach was used to develop a mathematical model describing the relationship between factors and responses of the drug delivery system and polymer-drug ratio was identified as a critical factor. Permeability studies using isolated bovine cornea, and biodistribution in whole bovine eyes suggested high bioavailability in the retina. The IOP-lowering effect of various H2S donors was evaluated in normotensive New Zealand albino rabbits. A H2S donor, OSL-4, was found to lower IOP by 26%, comparable than the marketed drug timolol (27%). Pretreating OSL-4 with glutathione further decreased the IOP by 32.3%. Lastly, the neuroprotective effects of H2S on the bovine retina were evaluated with H&E, TUNEL, glutathione, and superoxide dismutase assays. The biochemical assays reveal the ability of H2S to protect RGCs from oxidative stress-induced damage, attenuate oxidative stress, and upregulate glutathione. These results provide preliminary evidence that H2S can be an effective candidate for glaucoma.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2023

Author dc:creator

• Mhatre, Susmit

Advisors dc:contributor.advisor

• Opere, Catherine A.
• Singh, Somnath

• Glaucoma
• Hydrogen Sulfide
• Neuroprotection

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Repository record dc:identifier.uri

https://cdr.creighton.edu/handle/10504/153990

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/153990