17 Beta-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats.
This study aimed to assess the signaling pathway of the neuroprotective action of estrogen in the cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion. Rats received 17 beta-estradiol (1, 4 and 10 mg/kg, i.p.) 24 h before and 5 min after the completion of 2-h MCA occlusion. The cerebral infarct area was consistently observed in the cortex and striatum of the left hemisphere. Increased terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick-end labeling (TUNEL)-positive cells and DNA fragmentation in the penumbral zone were significantly reduced by 17 beta-estradiol. In line with these results, 17 beta-estradiol significantly increased Akt and cyclic AMP response element binding protein (CREB) with increased Bcl-2 protein in the ischemic area, whereas the elevated the phosphatase and tensin homolog deleted from chromosome10 (PTEN) phosphorylation was significantly reduced with decreased Bax protein and cytochrome c release. Inhibition of DNA fragmentation, PTEN phosphorylation, and Akt activation by 17 beta-estradiol were antagonized by iberiotoxin, a maxi-K channel blocker. Taken together, it is suggested that suppression of cerebral ischemic injury by 17 beta-estradiol may be ascribed to the maxi-K channel opening-coupled downregulation of PTEN phosphorylation and upregulation of Akt and CREB phosphorylation with resultant increase in Bcl-2 protein and decrease in Bax protein and cytochrome c release.
Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, Seo-Gu, Pusan 602-739, Korea.
Yeoung Cheul
YC
Choi
Jeong Hyun
JH
Lee
Ki Whan
KW
Hong
Kyu Sup
KS
Lee
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D002539:Cerebral Arterial Diseases / Q000150:complications; D002540:Cerebral Cortex / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000819:agonists*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D010455:Peptides / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000819:agonists*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D010455:Peptides; D026902:Potassium Channel Blockers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D004958:Estradiol; C064719:iberiotoxin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase