Protection of retinal ganglion cells in glaucoma: Current status and future

Highlights

• Glaucoma is a neurodegenerative disease that causes progressive retinal ganglion cell (RGC) death.

• Protection of RGCs can be a promising therapy for glaucoma.

• This review summarises the current literature in the field of protection of RGCs in glaucoma.

• This review discusses neuroprotective strategy of glaucoma for future clinical translation.

Abstract

Glaucoma is a neuropathic disease that causes optic nerve damage, loss of retinal ganglion cells (RGCs), and visual field defects. Most glaucoma patients have no early signs or symptoms. Conventional pharmacological glaucoma medications and surgeries that focus on lowering intraocular pressure are not sufficient; RGCs continue to die, and the patient's vision continues to decline. Recent evidence has demonstrated that neuroprotective approaches could be a promising strategy for protecting against glaucoma. In the case of glaucoma, neuroprotection aims to prevent or slow down disease progression by mitigating RGCs death and optic nerve degeneration. Notably, new pharmacologic medications such as antiglaucomatous agents, antibiotics, dietary supplementation, novel neuroprotective molecules, neurotrophic factors, translational methods such as gene therapy and cell therapy, and electrical stimulation-based physiotherapy are emerging to attenuate the death of RGCs, or to make RGCs resilient to attacks. Understanding the roles of these interventions in RGC protection may offer benefits over traditional pharmacological medications and surgeries. In this review, we summarize the recent neuroprotective strategy for glaucoma, both in clinical trials and in laboratory research.

Introduction

Glaucoma is a complex neurodegenerative disease that causes progressive retinal ganglion cell (RGC) death and optic nerve damage, which results in irreversible vision loss (Sah et al., 2017). About 67 million people worldwide suffer from this disease, and this number is increasing every year. By 2020 this number could reach 79 million, and by 2040 it is expected to affect 110 million people (Yap et al., 2018). It is the world's second-leading cause of blindness after cataracts (Flaxman et al., 2017), which places a heavy burden on patients' families and society. Some high-risk factors for the development of glaucoma include elevated intraocular pressure (IOP), genetics, ethnicity, high blood pressure, and obesity (Worley et al., 2011). According to the Glaucoma Research Foundation, there are several types of glaucoma, and the two main types are open-angel and angel-closure, which are characterized by increase IOP. Other types of glaucoma include normal-tension glaucoma (NTG), congential glaucoma, pigmentary glaucoma, traumatic glaucoma, and etc. RGCs are the neurons that transmit visual information from the retina to the brain. The pathogenesis of all forms of glaucoma is the loss of RGCs and their axons, and cupping of the optic nerve head (ONH). Increased production or decreased outflow of aqueous humor is responsible for IOP elevation, which is believed to be the main reason for the increased apoptosis of RGCs in glaucoma. Furthermore, RGCs cannot regenerate (Komáromy et al., 2021).

As such, current treatment strategies in the clinic mostly focus on lowering IOP, either via drugs or surgeries, then subsequently protecting against RGC loss. However, the outcome is not very satisfactory because RGCs continue to die even after IOP management. The mechanisms of RGCs apoptosis in glaucomatous conditions have been widely studied, including mitochondrial dysfunction (Lopez Sanchez et al., 2016), oxidative stress (Nita et al., 2016), endoplasmic reticulum stress and the unfolded protein response (Anholt et al., 2013), neurotrophin deficits (Almasieh et al., 2012), excitotoxicity (Casson, 2006), ischemia (Choi et al., 2015), inflammation, and glial activation (Mac Nair et al., 2015; Russo et al., 2016). This research suggests that neuroprotection, which protects against optic nerve (ON) damage and RGC death by mitigating the aforementioned mechanisms, may support IOP reduction by encouraging RGC survival, either through the provision of a nutritional environment for damaged RGCs or through the replacement of RGCs. Recent studies have shown that antiglaucomatous agents, antibiotics, dietary supplementation, novel neuroprotective molecules, neurotrophic factors (NTFs), gene therapy, cell-based therapy, and electrical stimulation therapy are able to protect against the loss of RGCs in glaucoma in vitro and in experimental animal models, as well as in some clinical trials. Therefore, in this review, we summarize the current literature in the field of neuroprotection in glaucoma and discuss the limitations and potential implications for clinical translation.