Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus.

Abstract	We here investigated endothelial nitric oxide synthase (eNOS) expression after 10 minutes of forebrain ischemia. Real-time polymerase chain reaction, immunoblots and immunohistochemical studies revealed up-regulation of eNOS expression in the hippocampal CA1 subfield of gerbil. Immunoreactivity of eNOS significantly increased in endothelium but neither in neurons nor astrocytes after 6 to 168 hours of reperfusion. An increased Akt activity preceded the postischemic eNOS up-regulation. Intracerebroventricular injection (i.c.v.) of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI-3K), significantly inhibited the increases in both eNOS mRNA and its protein with concomitant inhibition of Akt activation. The significant increase in the eNOS expression was also evident following preconditioning 2-minute ischemia. Both eNOS up-regulation and acquisition of ischemic tolerance observed at 3 days after preconditioning ischemia were significantly inhibited by pretreatment with wortmannin. Administration (i.c.v.) of N-nitro-L-arginine methyl ester, but not 7-nitroindazole, 30 minutes prior to lethal 10-minute ischemia, significantly abolished the acquired tolerance. Intraperitoneal injections of aminoguanidine at immediately after, 24, and 48 hours after preconditioning had no effects on the tolerance. These results suggest that eNOS expression is up-regulated in the endothelium via PI-3K pathways after transient forebrain ischemia, and that preconditioning-induced eNOS expression plays an important role in neuroprotection in the ischemic tolerance.
Authors	Akihito Hashiguchi, Shigetoshi Yano, Motohiro Morioka, Junichiro Hamada, Yukitaka Ushio, Yusuke Takeuchi, Kohji Fukunaga
Journal	Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 24 Issue 3 Pg. 271-9 (Mar 2004) ISSN: 0271-678X [Print] United States
PMID	15091107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Androstadienes Enzyme Inhibitors Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins Nitric Oxide Synthase Nitric Oxide Synthase Type III Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Protein Kinase C Protein Kinase C-alpha Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases Wortmannin
Topics	Androstadienes (metabolism) Animals Brain Ischemia (enzymology) Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinases (metabolism) Endothelium, Vascular (enzymology) Enzyme Inhibitors (metabolism) Gene Expression Regulation, Enzymologic Gerbillinae Hippocampus (cytology, enzymology) Ischemic Preconditioning Male Mitogen-Activated Protein Kinases (metabolism) Neurons (enzymology) Nitric Oxide Synthase (genetics, metabolism) Nitric Oxide Synthase Type III Phosphatidylinositol 3-Kinases (metabolism) Phosphoinositide-3 Kinase Inhibitors Protein Kinase C (metabolism) Protein Kinase C-alpha Protein Serine-Threonine Kinases Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Up-Regulation Wortmannin

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!