Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2.
After recent clinical trials, statins have gained increasing significance in secondary stroke prevention. From experimental studies, it is well established that statins have beneficial action when delivered prophylactically prior to a stroke. Conversely, much less is known about the effects of statins on injury development when delivered after ischemia. We here examined the effects of a post-ischemic delivery of rosuvastatin (0.5, 5 or 20 mg/kg, administered i.p. immediately after reperfusion onset), a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on brain injury and cell signaling after focal cerebral ischemia, induced by 90 min of intraluminal middle cerebral artery occlusion in mice. In animals receiving normal saline, 0.5 or 5 mg/kg rosuvastatin, middle cerebral artery occlusions resulted in reproducible brain infarcts at 24 h after reperfusion onset, which did not differ in size. However, rosuvastatin, administered at higher doses (20 mg/kg), reduced infarct volume at 24 and 48 h after ischemia (by 34+/-16% and 18+/-3%, respectively, P<0.05). Western blots revealed that rosuvastatin decreased phosphorylated extracellular-regulated kinase-1/-2 and reduced activated caspase-3 levels in ischemic brain areas, while endothelial NO synthase expression, p38 and Jun kinase phosphorylation were not influenced by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Rosuvastatin also significantly diminished expression levels of inducible NO synthase in the ischemic brain. Our results indicate that rosuvastatin may have utility not only as stroke prophylaxis but also as acute therapy inhibiting executive cell death pathways.
Kilic
U
U
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zurich, Switzerland. uelkan.kilic@usz.ch
Bassetti
C L
CL
Kilic
E
E
Xing
H
H
Wang
Z
Z
Hermann
D M
DM
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D020520:Brain Infarction / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000008:administration & dosage* / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000097:blood; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood; D015424:Reperfusion / Q000379:methods; D000068718:Rosuvastatin Calcium; D013194:Staining and Labeling; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3