Belen D, Besalti O, Yiğitkanli K, Kösemehmetoğlu K, Simşek S, Bolay H
Ministry of Health, Department of Neurosurgery, Diskapi Educational and Research Hospital, Ankara, Turkey.
Acta Neurochir (Wien). 2007 Oct;149(10):1041-7; discussion 1047-8. doi: 10.1007/s00701-007-1275-1. Epub 2007 Sep 17.
Though cerebral vasospasm is one of the most serious complications of subarachnoid haemorrhage (SAH), its complex pathogenesis is poorly understood and available clinical treatment options are unsatisfactory. This study was designed to examine the efficacy of leflunomide, an immunomodulatory agent with inhibitory properties, on vascular smooth muscle cell proliferation and inflammation in a rabbit cerebral vasospasm model.
Twenty-two adult New-Zealand rabbits were assigned to 4 groups: control, SAH, SAH plus vehicle, SAH plus leflunomide. Subarachnoid haemorrhage was induced by administration of 1 ml of fresh unheparinised autologous arterial blood into the cisterna magna. Oral leflunomide (2 mg/kg) or vehicle treatment was started 12 h after the induction of subarachnoid haemorrhage and administered once a day. Three days later, the animals were sacrificed and the basilar artery was examined histologically for the lumen area and the thickness of the vessel wall. Inflammatory reaction was also examined by counting white blood cells within the vessel wall by means of light microscopic examination using haematoxylin and eosin staining.
Severe and moderate vasospasms were detected in the basilar artery of the SAH and SAH plus vehicle treated groups, respectively. Leflunomide effectively reduced the vasospasm of the basilar artery. Compared to the vehicle treated group, leflunomide significantly reduced the lumen area (p < 0.01) and hyperplasia of the vessel wall (p < 0.01). Although inflammatory response within the vessel wall was reduced in the leflunomide treated group, no statistical significance was found between groups (p = 0.07).
This study demonstrates for the first time that leflunomide treatment attenuates cerebral vasospasm in a rabbit SAH model while inflammatory reaction in the vessel wall is not affected. Although further studies are needed to reveal its molecular mechanisms in relieving vasospasm, leflunomide may provide a therapeutic potential for human cerebral vasospasm induced by SAH.
尽管脑血管痉挛是蛛网膜下腔出血（SAH）最严重的并发症之一，但其复杂的发病机制仍未完全明确，现有的临床治疗方案也不尽人意。本研究旨在检测来氟米特（一种具有抑制特性的免疫调节剂）对兔脑血管痉挛模型中血管平滑肌细胞增殖和炎症的影响。
将22只成年新西兰兔分为4组：对照组、SAH组、SAH加赋形剂组、SAH加来氟米特组。通过向枕大池注入1ml新鲜未肝素化的自体动脉血诱导蛛网膜下腔出血。在蛛网膜下腔出血诱导后12小时开始口服来氟米特（2mg/kg）或赋形剂治疗，每天给药一次。三天后，处死动物，对基底动脉进行组织学检查，测量管腔面积和血管壁厚度。还通过苏木精-伊红染色的光镜检查对血管壁内的白细胞进行计数，以检测炎症反应。
SAH组和SAH加赋形剂治疗组的基底动脉分别检测到重度和中度血管痉挛。来氟米特有效减轻了基底动脉的血管痉挛。与赋形剂治疗组相比，来氟米特显著减小了管腔面积（p<0.01）并减轻了血管壁增生（p<0.01）。虽然来氟米特治疗组血管壁内的炎症反应有所减轻，但组间差异无统计学意义（p = 0.07）。
本研究首次表明，来氟米特治疗可减轻兔SAH模型中的脑血管痉挛，而血管壁内的炎症反应未受影响。尽管需要进一步研究来揭示其缓解血管痉挛的分子机制，但来氟米特可能为SAH所致的人类脑血管痉挛提供治疗潜力。
