Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Neurosurgery. 2010 Mar;66(3):551-9; discussion 559. doi: 10.1227/01.NEU.0000365771.89576.77.
Phosphodiesterase-4 (PDE-4) is a cyclic adenosine monophosphate-specific enzyme involved in various inflammatory diseases. We studied its role in and the effect of ibudilast, which predominantly blocks PDE-4, on rat cerebral aneurysms.
Cerebral aneurysms were induced at the anterior cerebral artery-olfactory artery bifurcation of female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The effect of ibudilast (30 or 60 mg/kg/d for 3 months) on their cerebral aneurysms was studied by morphological and immunohistochemical assessment and quantitative real-time polymerase chain reaction assay. In our in vitro study, we grew endothelial cells stimulated by angiotensin II under estrogen-free conditions and examined the effect of ibudilast on PDE-4 activation and the cyclic adenosine monophosphate level.
Morphological evaluation using vascular corrosion casts showed ibudilast significantly suppressed cerebral aneurysms in a dose-dependent manner. In rats with induced cerebral aneurysms, the gene and protein expression of PDE-4 was high, and endothelial leukocyte adhesion molecules (P-selectin, intracellular adhesion molecule 1, and vascular adhesion molecule 1), matrix metalloproteinase-9, and tumor necrosis alpha were expressed. Macrophage migration was also increased. Treatment with ibudilast down-regulated these molecules, suppressed macrophage migration into the aneurysm wall, and inhibited PDE-4 activation and the elevation of cyclic adenosine monophosphate in endothelial cells.
These results suggest that blocking of PDE4 is associated with the reduction of inflammation-related molecules and macrophage migration, thereby reducing the progression of cerebral aneurysms. It may represent a new conservative therapy to treat patients with cerebral aneurysms.
磷酸二酯酶-4（PDE-4）是一种参与多种炎症性疾病的环腺苷单磷酸特异性酶。我们研究了其在大鼠脑动脉瘤中的作用，以及主要阻断 PDE-4 的伊布地司特对大鼠脑动脉瘤的影响。
雌性大鼠在前脑动脉-嗅动脉分叉处诱导高血压、增加血流动力学应激和雌激素缺乏的脑动脉瘤。通过形态学和免疫组织化学评估以及定量实时聚合酶链反应检测，研究伊布地司特（30 或 60mg/kg/d，持续 3 个月）对其脑动脉瘤的影响。在我们的体外研究中，我们在无雌激素条件下培养受血管紧张素 II 刺激的内皮细胞，并检测伊布地司特对 PDE-4 激活和环腺苷单磷酸水平的影响。
血管腐蚀铸型的形态学评估表明，伊布地司特以剂量依赖的方式显著抑制脑动脉瘤。在诱导脑动脉瘤的大鼠中，PDE-4 的基因和蛋白表达水平较高，内皮白细胞黏附分子（P-选择素、细胞间黏附分子 1 和血管黏附分子 1）、基质金属蛋白酶-9 和肿瘤坏死因子-α也表达。巨噬细胞迁移也增加。伊布地司特治疗下调这些分子，抑制巨噬细胞迁移到动脉瘤壁，并抑制内皮细胞中 PDE-4 的激活和环腺苷单磷酸的升高。
这些结果表明，阻断 PDE4 与减少炎症相关分子和巨噬细胞迁移有关，从而减缓脑动脉瘤的进展。它可能代表一种治疗脑动脉瘤患者的新保守治疗方法。
