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

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.

• Authors: Zara Mehrabian, Yan Guo, Neil R Miller, Amanda D Henderson, Steven Roth, Steven L Bernstein
• Journal: Cells (Cells) Vol. 10 Issue 6 (06 09 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34207618 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo(d)(1,3)dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate
• Benzodioxoles
• Neuroprotective Agents
• Piperidines
• Prostaglandin Antagonists
• Meloxicam

Topics

• Animals
• Benzodioxoles (pharmacology, therapeutic use)
• Disease Models, Animal
• Male
• Meloxicam (pharmacology, therapeutic use)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Optic Neuropathy, Ischemic (drug therapy)
• Piperidines (pharmacology, therapeutic use)
• Prostaglandin Antagonists (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Retinal Ganglion Cells (drug effects)