Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma’s pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them.

Glaucoma is a leading cause of irreversible blindness worldwide. While intraocular pressure (IOP) presents a major risk factor, the underlying pathophysiology still remains largely unclear. The correlation between vascular abnormalities and glaucoma has been deliberated for decades. Evidence for a role played by vascular factors in the pathogenesis of glaucomatous neurodegeneration has already been postulated. In addition, the fact that glaucoma causes both structural and functional changes to retinal blood vessels has been described. This review aims to investigate the published evidence concerning the relationship between vascular abnormalities and glaucoma, and to provide an overview of the “chicken or egg” dilemma in glaucoma. In this study, several biomarkers of glaucoma progression from a vascular perspective, including endothelin-1 (ET-1), nitric oxide, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), were identified and subsequently assessed for their potential as pharmacological intervention targets.

Oxidative stress (OS) is an imbalance between free radicals/ROS and antioxidants, which evokes a biological response and is an important risk factor for diseases, in both the cardiovascular system and central nervous system (CNS). The underlying mechanisms driving pathophysiological complications that arise from OS remain largely unclear. The vascular endothelium is emerging as a primary target of excessive glucocorticoid and catecholamine action. Endothelial dysfunction (ED) has been implicated to play a crucial role in the development of neurodegeneration in the CNS. The retina is known as an extension of the CNS. Stress and endothelium dysfunction are suspected to be interlinked and associated with neurodegenerative diseases in the retina as well. In this narrative review, we explore the role of OS-led ED in the retina by focusing on mechanistic links between OS and ED, ED in the pathophysiology of different retinal neurodegenerative conditions, and how a better understanding of the role of endothelial function could lead to new therapeutic approaches for neurodegenerative diseases in the retina.

Purpose: The aim of this study was to explore the roles of crystallins in the context of aging in glaucoma and potential mechanisms of neuroprotection in an experimental animal model of glaucoma. Methods: Intraocular pressure (IOP) was significantly elevated for 8 weeks in animals at different ages (10 days, 12 weeks, and 44 weeks) by episcleral vein cauterization. Retinal ganglion cells (RGCs) were quantified by anti-Brn3a immunohistochemical staining (IHC). Proteomics using ESI-LTQ Orbitrap XL-MS was used to analyze the presence and abundance of crystallin isoforms the retinal samples, respectively. Neuroprotective property and localization of three selected crystallins CRYAB, CRYBB2, and CRYGB as most significantly changed in retina and retinal layers were determined by IHC. Their expressions and endocytic uptakes into Müller cells were analyzed by IHC and Western blotting. Müller cell secretion of neurotrophic factors into the supernatant following CRYAB, CRYBB2, and CRYGB supplementation in vitro was measured via microarray. Results: IOP elevation resulted in significant RGC loss in all age groups (P < 0.001). The loss increased with aging. Proteomics analysis revealed in parallel a significant decrease of crystallin abundance – especially CRYAB, CRYBB2, and CRYGB. Significant neuroprotective effects of CRYAB, CRYBB2, and CRYGB after addition to retinal cultures were demonstrated (P < 0.001). Endocytic uptake of CRYAB, CRYBB2, and CRYGB was seen in Müller cells with subsequent increased secretion of various neurotrophic factors into the supernatant, including nerve growth factor, clusterin, and matrix metallopeptidase 9. Conclusions: An age-dependent decrease in CRYAB, CRYBB2, and CRYGB abundance is found going along with increased RGC loss. Addition of CRYAB, CRYBB2, and CRYGB to culture protected RGCs in vitro. CRYAB, CRYBB2, and CRYGB were uptaken into Müller cells. Secretion of neurotrophic factors was increased as a potential mode of action.

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) significantly contributes to disease progression, managing IOP alone does not completely halt it. The mechanisms underlying RGCs loss in glaucoma remain unclear, but ferroptosis-an iron-dependent form of oxidative cell death-has been implicated, particularly in IOP-induced RGCs loss. There is an urgent need for neuroprotective treatments. Our previous research showed that hydrogen sulfide (H₂S) protects RGCs against glaucomatous injury. This study aims to investigate the interplay between elevated pressure, mitochondrial dysfunction, iron homeostasis, and ferroptosis in RGCs death, focusing on how H₂S may mitigate pressure-induced ferroptosis and protect RGCs. We demonstrate alterations in iron metabolism and mitochondrial function in a subacute IOP elevation model in vivo. In vitro, we confirm that elevated pressure, iron overload, and mitochondrial dysfunction lead to RGCs loss, increased retinal ferrous iron and total iron content, and heightened reactive oxygen species (ROS). Notably, pressure increases NADPH oxidase 2 (NOX2) and decreases glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. NOX2 deletion or inhibition by H₂S prevents pressure-induced RGCs loss and ferroptosis. Our findings reveal that H₂S chelates iron, regulates iron metabolism, reduces oxidative stress, and mitigates ferroptosis, positioning slow-releasing H₂S donors are positioning as a promising multi-target therapy for glaucoma, with NOX2 emerging as a key regulator of ferroptosis.

Oxidative stress (OS) damage can cause significant injury to cells, which is related to the occurrence and development of many diseases. This pathological process is considered to be the first step to trigger the death of outer retinal neurons, which is related to the pathology of retinal degenerative diseases. Hydrogen sulfide (H₂S) has recently received widespread attention as a physiological signal molecule and gas neuromodulator and plays an important role in regulating OS in eyes. In this article, we reviewed the OS responses and regulatory mechanisms of H₂S and its donors as endogenous and exogenous regulators in retinal degenerative diseases. Understanding the relevant mechanisms will help to identify the therapeutic potential of H₂S in retinal degenerative diseases.