Ocular hypertension-induced neurodegeneration is associated with upregulation of Prostaglandin E₂ receptor EP1 in the retina

Abstract

Purpose : Prostaglandin E₂ (PGE₂) plays key roles in driving inflammation, pain, and vascular events, and it is the primary target for inhibition by NSAIDs such as aspirin and ibuprofen. The role and regulation of PGE₂ in the retina is largely unknown. We investigate the expression and regulation of the PGE₂ pathway in the mouse retina/optic nerve during ocular hypertension (OHT) and the role of PGE₂ receptor EP1 in neuronal cells.

Methods : qPCR, Western Blot, immunohistochemistry, and LC-MS/MS were used to interrogate the PGE₂ pathway at various levels in vitro and in vivo. Temporal changes to the pathway were assessed in a mouse model of silicone oil-induced OHT from 1-8 wks. OHT-induced neurodegeneration was modeled in vitro by inducing glutamate excitotoxicity in the HT-22 mouse neuronal cell line. qPCR was used to validate HT-22 expression of the receptor EP1 and other genes in the PGE₂ pathway. HT-22 cells were treated with an EP1 agonist (17-phenyl trinor PGE₂) and viability was assessed.

Results : Sustained OHT led to 20% loss in GCL thickness by 8 wks. In the retina, the PGE₂ pathway was dynamically and temporally regulated across all time points. PGE₂ levels were significantly upregulated in both optic nerve (1.5-fold) and retina (2-fold) beginning at 4 wks (p < 0.05). At 6 wks, receptors EP2 and EP4 were significantly downregulated in the retina, however, retinal EP1 increased by ~30-fold. COX-2 showed early and transient expression in the retina and optic nerve during OHT. In vitro experiments demonstrated that glutamate stress significantly increased EP1 and COX-2 expression in neuronal cells while causing cell death. Neuronal cell death was triggered in a concentration-dependent manner following treatment with an EP1-selective agonist.

Conclusions :
Our results indicate for the first time that the PGE₂ pathway is present, functional, and dynamically regulated in retinas and optic nerves in response to OHT. Importantly, our findings have identified high expression of retinal EP1 as a key feature of OHT-induced neurodegeneration.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.