Molecular pathways in experimental glaucoma models

Abstract

Glaucoma is a complex and progressive disease that primarily affects the optic nerve axons, leading to irreversible vision loss. Although the exact molecular mechanisms underlying glaucoma pathogenesis are not fully understood, it is believed that except increased intraocular pressure, a combination of genetic and environmental factors play a role in the development of the disease. Animal models have been widely used in the study of glaucoma, allowing researchers to better understand the underlying mechanisms of the disease and test potential treatments. Several molecular pathways have been implicated in the pathogenesis of glaucoma, including oxidative stress, inflammation, and excitotoxic-induced neurodegeneration. This review summarizes the most important knowledge about molecular mechanisms involved in the glaucoma development. Although much research has been done to better understand the molecular mechanisms underlying this disease, there is still much to be learned to develop effective treatments and prevent vision loss in those affected by glaucoma.

Keywords: apoptosis; glaucoma; glaucoma models; neuroprotection; retinal ganglion cell.

Figure 1

Primary and secondary glaucoma animal models with consideration of IOP-impact.

Figure 2

The molecular pathways involved in animal glaucoma models at the level of retinal ganglion cell. TGF-β signaling: The canonical TGF-β signaling pathway begins with its binding to the type II receptor (TGF-βRII), which leads to phosphorylation and activation of the type I receptor (TGF-βRI). This process activates intracellular SMADs proteins (Smad2, Smad3, Smad4). The Smad complex moves to the cell nucleus, where it activates gene transcription, leading to the production of extracellular matrix. In trabecular meshwork cells, studies have shown that another important regulator, involved in TGF-β2-induced IOP increase, is Src kinase; the use of a potent Src inhibitor, Desatinib, resulted in alleviation of TGF-β2-induced IOP increase in rat eyes. Neurotrophins: The neurotrophic pathways provide support and protection to RGCs, and the loss of this support can contribute to the death of RGCs in glaucoma. The action of neurotrophins is mainly manifested through activation of two types of transmembrane glycoproteins, tropomyosin receptor kinases (TrkA, TrkB, and TrkC) and the low affinity neurotrophin receptor p75NTR. Trk activation triggers intricate signaling cascades, activating the Ras/ERK (extracellular signal-regulated kinase) pathway and stimulating mitogen-activated protein kinases (MAPs). Simultaneously, the PI-3 kinase/Akt pathway engages, and phospholipase C (PLC)-γ1 is activated (Mallone et al., 2020). The activation of p75NTR arises from the binding of immature precursor forms of neurotrophins (proNT), eliciting a dual effect on cell fate—either apoptosis or survival. This outcome is contingent upon the simultaneous expression of Trk receptors. Consequently, maintaining cellular homeostasis hinges on achieving equilibrium in the availability of proNTs and their mature counterparts, alongside the presence of both Trk and p75NTR receptors. Neuroinflammation: Microglia and astroglia are the cells involved in inflammatory mechanisms in the retina. Their function is to regulate ion concentration, metabolic support of neurons and neuroprotective activity. Microglia cells, once mature, can be activated by damage-associated molecular pathways (DAMPs), which are released by neuronal cells. In addition, increased IOP stimulates RGCs to produce and secrete heat shock proteins (HSPs). These factors stimulate microglial cells to secrete cytokines and chemokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and complement factors, which promote the morphological transformation of microglia into M1 (proinflammatory) and M2 (anti-inflammatory) macrophages. Inflammatory pathways are involved in the regulation of various genes that are upregulated in the retina. One of the regulatory factors is nuclear factor-kappa B (NF-κB)—it leads to upregulation of IL-1 cytokine family, IL-6 and TNF-α. TNF-α and another proapoptotic protein, FasL, have been implicated in the pathogenesis of glaucoma. Fas/FasL signaling: Fas ligand (FasL) is a protein that belongs to the TNF family. When bound to the Fas receptor, it causes induction of apoptotic and pro-inflammatory pathways. This pathway has been identified as involved in axonal degeneration, death of RGCs and induction of neuroinflammation in a chronic and induced mouse model of glaucoma. Another study used the small peptide molecule ONL1204, an antagonist of the Fas receptor, which was administered to mice by injection into the vitreous body. NADPH oxidase: Several recent studies have pointed to a significant role for NADPH oxidase (NOX) in oxidative stress during glaucoma. NOX has been identified as a major source of oxidative stress in many retinal eye diseases, such as age-related macular degeneration and ischemic retinopathy. Reactive oxygen species produced by NOX affect the regulation of various cellular processes such as proliferation, differentiation, and migration. Excitotoxicity: Glutamate plays an important function in regulating neurophysiological processes. However, increased stimulation of relevant receptors with glutamate leads to neuronal damage and death.