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

      Nicholson, James Daniel; Bernstein, Steven L. (2012)
      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.