Abstract 2177: Administration Of Pigment Epithelium-derived Factor Inhibits Cold Injury-induced Brain Edema In Mice
Brain edema is the life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with neuronal differentiating activity. We have found that PEDF inhibits advanced glycation end product-induced retinal vascular permeability by suppressing vascular endothelial growth factor (VEGF) production, thus proving a novel beneficial aspect of PEDF on diabetic retinopathy. In this study, we investigated whether and how PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a metal probe cooled with liquid nitrogen on parietal skull for 60 seconds. Cold injury significantly induced brain edema; water content of the brain was maximally increased 14 h after the injury, which was reduced by intraperitoneal injection of VEGF antibodies (Abs) or apocynin, an inhibitor of NADPH oxidase. PEDF mRNA and protein levels were up-regulated in response to cold injury. Intraperitoneal injection of PEDF dose-dependently inhibited the brain edema; 30 mg PEDF reduced the increase in brain water content by 40 %. Although VEGF and its receptor Flk-1 gene and/or protein expressions were not suppressed by PEDF, PEDF or anti-VEGF Abs inhibited the cold injury-induced NADPH oxidase activity in the brain. Further, PEDF inhibited activation of Rac-1, an essential component of NADPH oxidase in the cold injured-brain, while it did not affect mRNA levels of gp91phox, p22phox, or Rac-1. These results demonstrate that PEDF could inhibit the cold injury-induced brain edema by blocking the VEGF signaling to hyperpermeability through the suppression of NADPH oxidase via inhibition of Rac-1 activation. Our present study suggests that PEDF may be a novel therapeutic agent for the treatment of brain edema.