脳動脈瘤発生・増大のメカニズムとその抑制の可能性 : 実験的脳動脈瘤モデルを用いた知見から(<特集>脳動脈瘤に対する新たな考え方)  [in Japanese] Molecular Mechanisms for the Development of Intracranial Aneurysms and Its Possible Inhibition : From Findings Obtained by an Experimentally Induced Intracranial Aneurysm Model(<SPECIAL ISSUE>New Concept in Treatment for Cerebral Aneurysm)  [in Japanese]

近年,実験的脳動脈瘤モデルを用いた研究により脳動脈瘤の発生や増大が血管壁の炎症反応と密接に関係していることが明らかになってきた.脳動脈瘤発生の初期には,炎症関連転写因子であるNF-KBが内皮細胞で活性化され,MCP-1などの発現が亢進する.それにより,動脈瘤壁ヘマクロファージが集積し,MMPなどを分泌して,動脈瘤壁の退行性変化を促進するものと考えられる.高コレステロール血症治療薬であるスタチンは,上記の炎症関連因子の発現を低下させ,ラット脳動脈瘤に対する増大抑制効果をもつことが証明された.スタチンはヒト脳動脈瘤に対しても抑制効果をもつことが期待されるが,それを検証するための多施設臨床試験(SUAVe-PEGASUS研究)が現在行われている.

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-1) is up-regulated in rat IA walls at the early stage of IA formation, which is transactivated through nuclear factorkappa 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 "pleiotropic" 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.