Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats

Background and Purpose - The pathophysiology of cerebral aneurysms ( CAs) is linked to chronic inflammation and degradation of extracellular matrix in vascular walls. Because statins have protective effects on various vascular diseases independent of their lipid- lowering effects, we investigated the effect of simvastatin on CA progression. Methods - CAs were induced in Sprague- Dawley rats with or without oral administration of simvastatin. The size and media thickness of CAs was evaluated 3 months after aneurysm induction. Expression of macrophage chemoattractant protein- 1, vascular cell adhesion molecule- 1, endothelial nitric oxide synthase, interleukin- 1 beta, inducible nitric oxide synthase, matrix metalloproteinase- 2, and matrix metalloproteinase- 9 in aneurysmal walls was examined by reverse transcriptase - polymerase chain reaction and immunohistochemistry. To examine whether simvastatin has a suppressive effect on preexisting CAs, simvastatin administration started at 1 month after aneurysm induction. Results - Rats treated with simvastatin exhibited a significant increase in media thickness and a significant reduction in aneurysmal size compared with control rats. Treatment with simvastatin resulted in reduced expression of macrophage chemoattractant protein- 1 and vascular cell adhesion molecule- 1, increased expression of endothelial nitric oxide synthase, and reduced the number of macrophage infiltration. In quantitative polymerase chain reaction and immunohistochemistry, simvastatin significantly inhibited upregulated expression of interleukin- 1 beta, inducible nitric oxide synthase, matrix metalloproteinase- 2, and matrix metalloproteinase- 9 associated with CA progression. Gelatin zymography revealed decreased activity of matrix metalloproteinase- 2 and matrix metalloproteinase- 9 in aneurysmal walls by simvastatin treatment. Simvastatin also effectively inhibited aneurysm enlargement and thinning of the media of preexisting CAs. Conclusions - Treatment with simvastatin suppresses the development of CAs by inhibiting inflammatory reactions in aneurysmal walls. Simvastatin also has a preventive effect on the progression of preexisting CAs. Simvastatin is a promising candidate of a novel medical treatment for the prevention of CA progression.