Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury-induced brain edema in mice.
Brain edema is the most life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. We have recently found that administration of pigment epithelium-derived factor (PEDF) inhibits retinal hyperpermeability in rats by counteracting biological effects of vascular endothelial growth factor (VEGF). In this study, we investigated whether PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a pre-cooled metal probe on the parietal skull. VEGF and its receptor Flk-1 gene and/or protein expressions were up-regulated in the cold-injured brain. Cold injury induced brain edema, 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. PEDF dose-dependently inhibited the brain edema, whose effect was neutralized by simultaneous treatments with anti-PEDF Abs. Although VEGF and 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 treatment 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.
Jinnouchi
Yuko
Y
Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Yamagishi
Sho-ichi
S
Matsui
Takanori
T
Takenaka
Katsuhiko
K
Yoshida
Yumiko
Y
Nakamura
Kazuo
K
Ueda
Shin-ichiro
S
Imaizumi
Tsutomu
T
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003080:Cold Temperature / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D000098:Acetophenones; D000906:Antibodies; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D019255:NADPH Oxidases; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D020744:rac GTP-Binding Proteins; D000099174:Pigment Epithelium-Derived Factor; C056165:acetovanillone