Current Perspective of Hydrogen Sulfide as a Novel Gaseous Modulator of Oxidative Stress in Glaucoma

Abstract

Glaucoma is a group of diseases characterized by the progressive loss of retinal ganglion cells and their axons. Elevated intraocular pressure (IOP) is the main clinical manifestation of glaucoma. Despite being in the focus of the studies for decades, the characteristic and the exact pathology of neurodegeneration in glaucoma remains unclear. Oxidative stress is believed to be one of the main risk factors in neurodegeneration, especially its damage to the retinal ganglion cells. Hydrogen sulfide (H₂S), the recently recognized gas signaling molecule, plays a pivotal role in the nervous system, vascular system, and immune system. It has also shown properties in regulating oxidative stress through different pathways in vivo. In this review, we summarize the distribution and the properties of H₂S within the eye with an emphasis on its role in modulating oxidative stress in glaucoma.

Keywords: glaucoma; hydrogen sulfide; neurodegeneration; oxidative stress.

Figure 1

Endogenous H₂S is produced through two main pathways, the non-enzymatic pathway and the enzymatic pathway. The non-enzymatic pathway is produced in erythrocytes via the glucose oxidation pathway. The enzymatic pathway promotes the production of H₂S from cysteine with four common enzymes (cystathionine-β-lyase (CBS), cystathionine-γ-synthase (CSE), 3-mercapto-methylthio pyruvate aminotransferase (3MST), and cysteine aminotransferase (CAT)). These enzymes are distributed in various tissues of the body.

Figure 2

The anti-oxidative properties of H₂S in glaucoma. The effect of H₂S on glaucoma is mainly reflected in three aspects. (1) By regulating the autonomic nerves and reducing the release of sympathetic nerves, it reduces the production of aqueous humor (AH) and promotes the flow of AH to lowering intraocular pressure (IOP). (2) Through the relaxation of vascular smooth muscles, stabilize intraocular perfusion and reduce ischemia-reperfusion injury. (3) By regulating iron homeostasis, regulating mitochondrial function, and reducing the toxicity of glutamate, it reduces the generation of ROS to prevent nerve degenerative changes.

Figure 3

H₂S promotes the synthesis of glutathione in cells through three pathways. (1) H₂S suppresses the extracellular competition between glutamate and cystine, therefore promotes cystine (the substrate of glutathione (GSH) synthesis) entering the cells. (2) H₂S promotes the production of a variety of glutathione synthase and increases the concentration of GSH in the cell. (3) H₂S indirectly promotes the synthesis of GSH through the Nrf2-dependent pathway.