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
Abstract
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.
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Statins have neurorestorative properties, including promotion of neuronal survival, angiogenesis, and neurogenesis.
“Statins also have neurorestorative properties (ie, promotion of neuronal survival, angiogenesis, and neurogenesis).36,89”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [89]
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Self-citation
- Authors
- Kilic, Ü., Bassetti, C. L., Kilic, E., Xing, H., Wang, Z., & Hermann, D. M.
- Affiliations
- University Hospital Zurich (CH)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 134
- Issue
- 3
- Pages
- 901-906
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2013105910
- Cited by
- 43
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2019: 1 · 2017: 1 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 8
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- rosuvastatin, statins, focal cerebral ischemia, middle cerebral artery occlusion, ERK1/2 phosphorylation, caspase-3, neuronal cell death, infarct size, inducible nitric oxide synthase, p38 MAPK, Jun kinase, secondary stroke prevention, acute stroke therapy
- MeSH terms
- Rosuvastatin Calcium, Animals, Cell Count, Brain Ischemia, Dose-Response Relationship, Drug, Fluorobenzenes, Male, Mice, Inbred C57BL, Pyrimidines, Staining and Labeling, Sulfonamides, Time Factors, Blotting, Western, Reperfusion, Laser-Doppler Flowmetry, Nitric Oxide Synthase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mitogen-Activated Protein Kinase 1, Infarction, Middle Cerebral Artery, Brain Infarction, Mitogen-Activated Protein Kinase 3, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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