Molecular mechanisms for the development of intracranial aneurysms and its possible inhibition: From findings obtained by an experimentally induced intracranial aneurysm model

Abstract

Subarachnoid hemorrhage (SAH) resulting from rupture of an intracranial aneurysm (IA) is one of the most devastating forms of stroke. Given the catastrophic sequelae after subarachnoid hemorrhage, developing a novel therapeutic modality which prevents IA progression and rupture is imperative. Results from studies using an experimentally induced intracranial aneurysm model have provided us a wide variety of evidence supporting the notion that IA is closely associated with inflammation. Expression of monocyte chemotactic protein-1 (MCP-l) is up-regulated in rat IA walls at the early stage of IA formation, which is transactivated through nuclear factor- kappa B (NF-/κB), a family of transcriptional factors regulating various proinflammatory genes. MCP~1 recruits macrophages into aneurysmal walls, which secretes matrix metalloproteinases (MMPs) -2 and -9 causing degradation of the extracellular matrix in IA walls. Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), widely used cholesterol-lowering drugs, have vascular protective effects known as "pleio- tropic" effects. Treatment with statins suppresses the development of rat IAs by inhibiting inflammatory reactions in aneurysmal walls. Statin also has a preventive effect on the progression of preexisting rat IAs. Therefore, statin is a promising candidate of a novel medical treatment for the prevention of IA progression and rupture. A multi-center prospective randomized trial examining the inhibitory effect of statins on progression and rupture of human IAs, Small Unruptured Aneurysm Verification-Prevention Effect against Growth of cerebral Aneurysm Study Using Statin (SUAVe-PEGASUS) study is now ongoing.