Biomol Ther.  2015 Nov;23(6):531-538. 10.4062/biomolther.2015.124.

Simvastatin Reduces Lipopolysaccharides-Accelerated Cerebral Ischemic Injury via Inhibition of Nuclear Factor-kappa B Activity

• Anthony Jalin AMA
• Lee JC
• Cho GS
• Kim C
• Ju C
• Pahk K
• Song HY
• Kim WK

• KMID: 2380304
• DOI: http://doi.org/10.4062/biomolther.2015.124

Abstract

Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-1beta in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-kappaB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IkappaB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.

Keyword

Simvastatin; Cerebral Stroke; Cytokine; Inflammation; Macrophages; Microglia

MeSH Terms

Animals
Brain
Corpus Callosum
Inflammation
Lipopolysaccharides
Macrophages
Meningitis, Bacterial
Microglia
Microinjections
Monocytes
NF-kappa B
Oxidoreductases
Rats
Simvastatin*
Stroke
Vascular Diseases
Lipopolysaccharides
NF-kappa B
Oxidoreductases
Simvastatin