EDG receptors as a potential therapeutic target in retinal ischemia-reperfusion injury.

Abstract

LPA (lysophosphatidic acid) specific endothelial differentiation gene (EDG) receptors have been implicated in various anti-apoptotic pathways. Ischemia of the brain and retina causes neuronal apoptosis, which raises the possibility that EDG receptors participate in anti-apoptotic signaling in ischemic injury. We examined the expression of EDG receptors in a model of retinal ischemia-reperfusion injury and also tested LXR-1035, a novel analogue of LPA, in the rat following global retinal ischemic injury. Rats were subjected to 45 or 60 min of raised intraocular pressure. Animals were sacrificed at 24 h post-ischemia and retinal tissue was stained for EDG receptors. In separate experiments, animals were randomized to receive LXR or saline vehicle by intravitreal injection 24 h prior to ischemia. The degree of retinal damage was assessed morphologically by measuring the thickness of the inner retinal layers as well as functionally by electroretinography (ERG). We found that the normal retina has a baseline expression of the LPA receptors, EDG-2 and EDG-4, which are significantly upregulated in the inner layers in response to ischemia. Animals pretreated with LXR-1035 had dose-dependent, significant reductions in histopathologic damage and significant improvement in functional deficits compared with corresponding vehicle-controls, after 45 and 60 min of ischemia. These results suggest that LPA receptor signaling may play an important role in neuroprotection in retinal ischemia-reperfusion injury.

• Authors: Sean I Savitz, Manjeet S Dhallu, Samit Malhotra, Antonios Mammis, Lenore C Ocava, Pearl S Rosenbaum, Daniel M Rosenbaum
• Journal: Brain research (Brain Res) Vol. 1118 Issue 1 Pg. 168-75 (Nov 06 2006) ISSN: 0006-8993 [Print] Netherlands
• PMID: 17026968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LXR 1035
• Lysophospholipids
• Neuroprotective Agents
• Receptors, Lysophosphatidic Acid
• Receptors, Lysosphingolipid
• lysophosphatidic acid

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain Ischemia (drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electroretinography
• Intraocular Pressure (physiology)
• Lysophospholipids (metabolism, pharmacology)
• Male
• Nerve Degeneration (drug therapy, metabolism, physiopathology)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Lysophosphatidic Acid (drug effects, metabolism)
• Receptors, Lysosphingolipid (drug effects, metabolism)
• Reperfusion Injury (drug therapy, metabolism, physiopathology)
• Retinal Diseases (drug therapy, metabolism, physiopathology)
• Signal Transduction (drug effects, physiology)
• Treatment Outcome