PITAVASTATIN SUPPRESSES FORMATION AND PROGRESSION OF CEREBRAL ANEURYSMS THROUGH INHIBITION OF THE NUCLEAR FACTOR κB PATHWAY

OBJECTIVE: Recent investigations strongly suggest that the pathophysiology of cerebral aneurysms (CA) is closely associated with chronic inflammation in vascular walls. Nuclear factor kappa B (NF-kappa B) has a key role in the formation and progression of CAs. Because statins exert anti-inflammatory effects in various vascular diseases, we investigated the effect of pitavastatin on NF-kappa B activation and CA formation in experimentally induced CAs in rats. METHODS: CAs were induced in Sprague-Dawley rats with or without administration of pitavastatin (4 mg/kg/d orally). Size, change of internal elastic lamina, and rnedia thickness of induced CAs were measured in both groups after aneurysm induction. The effects of pitavastatin on NF-kappa B activation in aneurysmal walls were examined by immunohistochemistry and gel shift assay. Expression of downstream genes was analyzed by quantitative polymerase chain reaction and immunohistochemistry. To examine whether pitavastatin has a suppressive effect on preexisting CAs, pitavastatin administration started 1 month after aneurysm induction. RESULTS: Pitavastatin treatment significantly prevented CA progression (P < 0.01) and NF-kappa B activation in aneurysmal walls. Expression of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, interleukin-1 beta, inducible nitric oxide synthase, and matrix metalloproteinase-9 in aneurysmal walls was also inhibited by pitavastatin. Pitavastatin treatment led to media thickening in preexisting CAs. CONCLUSION: Pitavastatin has a suppressive effect on CA progression through the inhibition of NF-kappa B activation in aneurysmal walls. Moreover, pitavastatin treatment can cause the regression of degenerative changes in preexisting CA walls. Pitavastatin is a promising candidate for a novel preventive agent against subarachnoid hemorrhage.