Hypothermia blocks beta-catenin degradation after focal ischemia in rats.
Dephosphorylated and activated glycogen synthase kinase (GSK) 3beta hyperphosphorylates beta-catenin, leading to its ubiquitin-proteosome-mediated degradation. beta-catenin-knockdown increases while beta-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of beta-catenin are reduced in the brain of Alzheimer's patients. However, whether beta-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK 3beta and beta-catenin, and the protective effect of moderate hypothermia (30 degrees C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK 3beta was dephosphorylated at 5 and 24 h after stroke in the normothermic (37 degrees C) brain; hypothermia augmented GSK 3beta dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK 3beta dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK 3beta protein. Corresponding to GSK 3beta activity in normothermic rats, beta-catenin phosphorylation transiently increased at 5 h in both the ischemic penumbra and core, and the total protein level of beta-catenin degraded after normothermic stroke. Hypothermia did not inhibit beta-catenin phosphorylation, but it blocked beta-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize beta-catenin, which may contribute to the protective effect of moderate hypothermia.
Zhang
Hanfeng
H
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5327, USA.
Ren
Chuancheng
C
Gao
Xuwen
X
Takahashi
Tetsuya
T
Sapolsky
Robert M
RM
Steinberg
Gary K
GK
Zhao
Heng
H
D000818:Animals; D001831:Body Temperature; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D020520:Brain Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D002560:Cerebrovascular Circulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3