McGirt Matthew J, Pradilla Gustavo, Legnani Federico G, Thai Quoc-Anh, Recinos Pablo F, Tamargo Rafael J, Clatterbuck Richard E
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Neurosurgery. 2006 May;58(5):945-51; discussion 945-51. doi: 10.1227/01.NEU.0000210262.67628.7E.
Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH.
New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy.
In vehicle treated rabbits, mean +/- standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 +/- 0.08 mm versus 0.75 +/- 0.03 mm, P < 0.01). After SAH, mean +/- standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 +/- 0.04 mm versus 0.49 +/- 0.08 mm, P < 0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean +/- standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 +/- 2; SAH-vehicle 90 +/- 27; P < 0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 +/- 13; SAH vehicle, 90 +/- 27; P < 0.001).
Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.
实验证据表明，细胞间黏附分子-1介导的白细胞外渗参与了脑血管痉挛的发病机制。辛伐他汀是一种HMG-CoA还原酶抑制剂，可降低细胞间黏附分子-1的表达，并竞争性抑制白细胞与细胞间黏附分子-1的结合。我们假设在蛛网膜下腔出血（SAH）发作后给予辛伐他汀可减轻兔SAH模型中血管周围粒细胞的迁移并改善脑血管痉挛。
15只新西兰白兔接受了向小脑延髓池注射自体血或假手术，然后在SAH或假手术后30分钟、24小时和48小时皮下注射辛伐他汀（40mg/kg）或赋形剂。72小时后，通过原位灌注/固定和图像分析测量基底动脉管腔直径。在光学显微镜下对用CD-18单克隆抗体染色的血管周围粒细胞和巨噬细胞进行计数。
在接受赋形剂治疗的兔子中，SAH后3天（n=5）与假手术（n=5）兔子相比，平均±标准差的基底动脉直径减小（0.49±0.08mm对0.75±0.03mm，P<0.01）。SAH后，辛伐他汀治疗组（n=5）兔子的平均±标准差基底动脉直径大于赋形剂治疗组（n=5）（0.63±0.04mm对0.49±0.08mm，P<0.01）。在接受赋形剂治疗的兔子中，SAH导致血管周围CD18细胞平均计数±标准差增加（假手术-赋形剂组，2.8±2；SAH-赋形剂组90±27；P<0.01）。皮下给予辛伐他汀可减轻SAH后血管周围CD18阳性细胞的这种增加（SAH-他汀组，41.6±13；SAH-赋形剂组，90±27；P<0.001）。
SAH发作后皮下给予辛伐他汀可减轻兔实验性SAH后血管周围粒细胞的迁移并改善基底动脉血管痉挛。5-羟-3-甲基戊二酰辅酶A还原酶抑制剂，如辛伐他汀，可能潜在地用作预防SAH后脑血管痉挛的药物。
