Mechanisms Regulating Edema in Anterior Ischemic Optic Neuropathy and Approaches to Treatment

Abstract

There are few clinically effective approaches that reduce CNS white matter (WM) injury. Following WM infarct, nuclear factor κB (NFκB)-driven pro-inflammatory signaling can amplify vascular injury, resulting in progressive endothelial dysfunction and a severe ischemic lesion. I evaluated whether amplification of vascular injury in WM could be reduced using complementary approaches related to NFκB signaling: 1) I administered the anti-inflammatory compound 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a prostaglandin known to inhibit NFκB nuclear translocation; 2) I investigate the role of sulfonylurea receptor 1 (SUR1), which is reported to contribute to vascular dysfunction by opening a non-specific cation channel in response to NFκB signaling. I evaluated the effects of 15d-PGJ2 in the rodent anterior ischemic optic neuropathy (rAION) model, an in vivo optic nerve (ON) ischemia model that shares many characteristics with the clinical condition non-arteritic anterior ischemic optic neuropathy (NAION). I found that 15d-PGJ2 administered intravenously, either acutely or 5 hours post-insult, reduced tissue edema and significantly increased survival of retinal ganglion cells (RGCs) 30 days post-rAION. I developed a novel quantitative capillary vascular analytical technique which allowed me to show that 15d-PGJ2 improves ON capillary perfusion at 1 day post-infarct. To investigate the mechanism of 15d-PGJ2 action, I developed an immunohistochemical technique that enabled me to directly determine that 15d-PGJ2 acts to reduce NFκB signaling in white matter by preventing nuclear localization of the NFκB p65 subunit. Western blot analysis and qRT-PCR gene expression analysis confirmed the 15d-PGJ2-associated reduction of NFκB signaling. SUR1 upregulation after other types of CNS focal ischemic events has been associated with edema formation. Because edema is associated with rAION, I evaluated SUR1 expression post-ON infarct using immunohistochemistry, western blot analysis, and quantitative real time polymerase chain reaction (qRT-PCR). I found no evidence that SUR1 is upregulated in WM after rAION. Using the SUR1 modulator glibenclamide, a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes, I found no difference in ON edema with and without glibenclamide treatment. My results show that, while 15d-PGJ2-associated NFκB modulation may be a useful approach for reducing ON ischemic injuries, increased NFκB signaling apparently does not result in sulfonylurea receptor 1 (SUR1) upregulation in the ON under the conditions tested. These studies may have importance for improved clinical treatment of NAION and other WM ischemic events.