ABSTRACT
Purpose: Glaucoma is a leading cause of irreversible blindness. Glaucomatous intraocular pressure (IOP) triggers deleterious effects, including gliosis, optic nerve (ON) axonal retraction, neurotrophic factor deprivation, inflammation, and other pathological events, leading to retinal ganglion cell (RGC) loss. Trophic factor impairment enhances RGC apoptosis susceptibility. Neuritin 1 (NRN1), a neurotrophic protein downstream of various neurotrophins, exhibited RGC protection and regeneration in axotomy models. We evaluated human recombinant NRN1's impact on human RGCs cultured in pressurized conditions within the ex vivo translaminar autonomous system to simulate glaucoma pathogenesis. Methods: Human glaucomatous and non-glaucomatous donor eyes were obtained from eye banks according to the Declaration of Helsinki. Initially, we evaluated NRN1and RGC marker expression in glaucoma and non-glaucomatous retina to determine the NRN1 level and its association with RGC loss. Further, we evaluated NRN1's therapeutic potential by treating pressurized human eyes at normal and high IOP for seven days. Retina, ON, and conditioned medium were analyzed for RGC survival (THY1, RBPMS), gliosis (GFAP), apoptosis (CASP3, CASP7), and extracellular matrix deposition (COLIV, FN) by qRT-PCR and western blotting. Paraphenylenediamine staining assessed ON axonal degeneration, whereas ex vivo electroretinogram assessed retinal activity. Results: Glaucomatous retinas exhibited significant reductions in both NRN1 (*p = 0.007, n = 5) and RGC marker expression (*p = 0.04, n = 5). NRN1 treatment reduced gliosis, extracellular matrix deposition, ON degeneration, and increased retinal activity in pressure-perfused eyes. Conclusions: Our study confirms that NRN1 enhances human RGC survival and improves retinal function in degenerative conditions, substantiating it as a promising candidate for rescuing human RGCs from degeneration.
ABSTRACT
Glaucoma is a group of optic neuropathies and the world's leading cause of irreversible blindness. Normal-tension glaucoma (NTG) is a subtype of glaucoma that is characterized by a typical pattern of peripheral retinal loss, in which the patient's intraocular pressure (IOP) is considered within the normal range (<21 mmHg). Currently, the only targetable risk factor for glaucoma is lowering IOP, and patients with NTG continue to experience visual field loss after IOP-lowering treatments. This demonstrates the need for a better understanding of the pathogenesis of NTG and underlying mechanisms leading to neurodegeneration. Recent studies have found significant connections between NTG and cerebral manifestations, suggesting NTG as a neurodegenerative disease beyond the eye. Gaining a better understanding of NTG can potentially provide new Alzheimer's Disease diagnostics capabilities. This review identifies the epidemiology, current biomarkers, altered fluid dynamics, and cerebral and ocular manifestations to examine connections and discrepancies between the mechanisms of NTG and Alzheimer's Disease.
