Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron.
Pretreatment with a low intracerebral dose of thrombin reduces brain edema after hemorrhagic and thrombo-embolic stroke. We have termed this phenomena thrombin preconditioning (TPC) or thrombin-induced brain tolerance. Red blood cell lysis and iron overload contribute to delayed edema formation after intracerebral hemorrhage. The present study examined whether TPC can attenuate the brain edema induced by lysed red blood cells or iron. It also examined whether TPC is associated with increasing hypoxia inducible factor-1alpha (HIF-1alpha) levels and alterations in two HIF-1alpha target genes, transferrin (Tf) and transferrin receptor (TfR), within the brain. Brain edema was measured by wet/dry weight method. HIF-1alpha, Tf, and TfR were measured by Western blot analysis and immunohistochemistry. We found that TPC reduces the edema induced by infusion of lysed red blood cells and iron. Thrombin increases HIF-1alpha levels through p44/42 mitogen activated protein kinases pathway. Thrombin also increases Tf and TfR levels in the brain. These results indicate that HIF-1alpha and its target genes may be involved in thrombin-induced brain tolerance.
Hua
Ya
Y
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Keep
Richard F
RF
Hoff
Julian T
JT
Xi
Guohua
G
D000818:Animals; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D006461:Hemolysis; D006490:Hemostatics / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D006490:Hemostatics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011990:Receptors, Transferrin; D014157:Transcription Factors; D014168:Transferrin; D007501:Iron; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin