The protective effect of early hypothermia on PTEN phosphorylation correlates with free radical inhibition in rat stroke.
We recently showed that intraischemic moderate hypothermia (30 degrees C) reduces ischemic damage through the Akt pathway after permanent distal middle cerebral artery occlusion in rats. The only Akt pathway component preserved by hypothermia is phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN), which suggests that p-PTEN may have a central role in neuroprotection. Reactive oxygen species (ROS) are critically involved in mediating ischemic damage after stroke by interacting with signaling molecules, including Akt, PTEN, and delta-protein kinase C (PKC). We investigated the protective mechanisms of moderate hypothermia on these signaling proteins after transient focal ischemia in rats. Early moderate hypothermia (3 h) was administered 15 mins before reperfusion, and delayed moderate hypothermia (3 h) was applied 15 mins after reperfusion. Our results indicate that early hypothermia reduced infarction, whereas delayed hypothermia did not. However, both early and delayed hypothermia maintained levels of Mn-SOD (superoxide dismutase) and phosphorylated Akt and blocked delta-PKC cleavage, suggesting that these factors may not be critical to the protection of hypothermia. Nevertheless, early hypothermia preserved p-PTEN levels after reperfusion, whereas delayed hypothermia did not. Furthermore, ROS inhibition maintained levels of p-PTEN after stroke. Together, these findings suggest that phosphorylation levels of PTEN are closely associated with the protective effect of early hypothermia against stroke.
Lee
Sang Mi
SM
Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, California 94305-5327, USA.
Zhao
Heng
H
Maier
Carolina M
CM
Steinberg
Gary K
GK
D000818:Animals; D001557:Benzenesulfonates / Q000378:metabolism; D007036:Hypothermia, Induced; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D001557:Benzenesulfonates; D017382:Reactive Oxygen Species; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D051059:PTEN Phosphohydrolase