Nifedipine Inhibits the Progression of An Experimentally Induced Cerebral Aneurysm in Rats with Associated Down-Regulation of NF-Kappa B Transcriptional Activity

Tomohiro      Aoki; Hiroharu      Kataoka; Ryota      Ishibashi; Kazuhiko      Nozaki; Nobuo      Hashimoto

Abstract

Cerebral aneurysm (CA) causes a life-threatening subarachnoid hemorrhage. However, no effective medical treatment to prevent the growth of CA is available. Nifedipine, a widely used calcium antagonist, was shown to improve endothelial function in various cardiovascular diseases. We examined whether nifedipine has a protective effect on CA progression. CAs were experimentally induced in Sprague-Dawley rats followed by intraperitoneal injection of either 10mg/kg of nifedipine per day or vehicle. The size and media thickness of CAs were measured one month after aneurysm induction. NF-kappa B (NF-κB) activity in aneurysmal walls was assessed by immunohistochemistry for activated NF-κB p65 subunit and electrophoretic mobility shift assay (EMSA). Expression of monocyte chomoattractant protein-1 (MCP- 1) and matrix metalloproteinase (MMP) -2 in aneurysmal walls was examined by RT-PCR and immunohistochemistry. To examine whether nifedipine has a suppressive effect on preexisting CAs, nifedipine administration started at one month after aneurysm induction and pathological changes were assessed at two months after aneurysm induction. Aneurysm size was smaller and the media was thicker in the nifedipine-treated group even though blood pressure was not different between groups. Nifedipine inhibited DNA binding of NF-κB in aneurysmal walls. As regards MCP-1 expression and macrophage, which is the main inflammatory cell in the aneurysmal walls, infiltration into aneurysmal walls was decreased by nifedipine. Immunohistochemistry and gelatin zymography showed that the expression and activity of MMP-2 was also reduced by nifedipine. Furthermore, nifedipine significantly prevented the enlargement and degeneration of aneurysmal walls of preexisting CAs. Nifedipine may be useful as a medical drug for patients with CAs.

Keywords: Animal model, Ca blocker, cerebral aneurysm, inflammation, macrophage, matrix metalloproteinase, NF-kappaB, nifedipine