Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy.

Zara Mehrabian,Steven L Bernstein,Neil R Miller,Yan Guo,Steven Roth,Amanda D Henderson

doi:10.3390/cells10061440

Abstract

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection.

Highlights

IntroductionNonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior portion of the optic nerve (the optic nerve head; ONH), and the most common cause of sudden optic nerve-related vision loss in individuals over the age of 50 [1]
We previously demonstrated that pharmacological doses of the anti-inflammatory prostaglandin J2 (PGJ2 ), which is nonenzymatically derived from PGD2, neuroprotect in the rodent and primate models of Nonarteritic anterior ischemic optic neuropathy (NAION) [7,8], and that this effect appears to occur by reducing post-rodent NAION model (rAION) inflammation
We performed a comparison of expression between rAION-induced, PGJ2 and vehicle-treated optic nerve head (ONH), which revealed that 203 genes were upregulated and 306 genes downregulated between the two groups (Figure 1B), and between PGJ2 -treated and naïve groups (Figure 1C)

Summary

Introduction

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior portion of the optic nerve (the optic nerve head; ONH), and the most common cause of sudden optic nerve-related vision loss in individuals over the age of 50 [1]. NAION cases are hypothesized to occur following initial vascular dysregulation, which results in capillary decompensation with development of edema in the restricted ONH space. The subsequent edema generates an ONH-compartment syndrome with vascular compression and axonal ischemia [2,3], which causes a loss of retinal ganglion cell (RGC) neurons and their axons. No clinically proven effective treatments exist for this disorder [4], multiple approaches have been tried, including steroids, memantine, vascular endothelial growth factor inhibitors, and more recently a phase 2/3 clinical trial using siRNA against caspase 2

Methods

Results

Conclusion