Chang Chih-Zen, Dumont Aaron S, Simsek Serkan, Titus Brian J, Kwan Aij-Lie, Kassell Neal F, Solenski Nina J
Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Neurosurgery. 2007 Jun;60(6):1110-7; discussion 1117-8. doi: 10.1227/01.NEU.0000255467.22387.5C.
Selective adenosine 2A receptor agonists, such as ATL-146e, are known to be potent anti-inflammatory agents devoid of systemic side effects and have been used clinically in a number of disease states. However, adenosine 2A receptor agonists have not been studied in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The present study investigated the efficacy of ATL-146e in the prevention of leukocyte infiltration and attenuation of posthemorrhagic vasospasm.
The rodent femoral artery model of vasospasm was used. Forty male Sprague-Dawley rats were randomly assigned to four different groups (vehicle, 1 ng/kg/min, 10 ng/kg/min, or 100 ng/kg/min ATL-146e administered via subcutaneous osmotic minipump). Vasospasm was evaluated at posthemorrhage Day 8 (period of peak constriction) by calculating the lumen cross-sectional area (expressed as percent change in luminal area: ratio of blood-exposed vessel to normal saline-exposed vessel) and radial wall thickness. Immunostaining with anti-CD45 monoclonal antibody to detect leukocytes was used to evaluate localized inflammation.
Significant vasospasm was noted in the vehicle-treated (blood-exposed) control group (78.5%, P < 0.001; expressed as a ratio of luminal area of the saline [no blood] control), but not in the ATL-146e-treated groups (lumen ratio to control: 105.0, 83.4, and 91.3% for the 1, 10, and 100 ng/kg/min groups, respectively). Additionally, infiltration of inflammatory cells was reduced significantly and radial wall thickness was decreased in the ATL-146e-treated groups compared with the vehicle-treated control group.
Selective activation of the adenosine 2A receptor with ATL-146e prevented posthemorrhagic vasospasm and reduced leukocyte infiltration in this experimental model. This agent is worthy of further investigation and lends credence to the hypothesis supporting a role for inflammation in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage.
选择性腺苷2A受体激动剂，如ATL-146e，已知是强效抗炎药，无全身副作用，已在多种疾病状态中临床应用。然而，腺苷2A受体激动剂尚未在蛛网膜下腔出血后脑血管痉挛的治疗中进行研究。本研究调查了ATL-146e在预防白细胞浸润和减轻出血后血管痉挛方面的疗效。
采用啮齿动物股动脉血管痉挛模型。40只雄性Sprague-Dawley大鼠随机分为4组（分别通过皮下渗透微型泵给予赋形剂、1 ng/kg/min、10 ng/kg/min或100 ng/kg/min的ATL-146e）。在出血后第8天（收缩高峰期）通过计算管腔横截面积（以管腔面积变化百分比表示：血液暴露血管与生理盐水暴露血管的比值）和径向壁厚度评估血管痉挛情况。使用抗CD45单克隆抗体免疫染色检测白细胞，以评估局部炎症。
赋形剂处理（血液暴露）的对照组出现显著血管痉挛（78.5%，P < 0.001；以生理盐水[无血液]对照组的管腔面积比值表示），但在ATL-146e处理组中未出现（1、10和100 ng/kg/min组的管腔与对照组比值分别为105.0%、83.4%和91.3%）。此外，与赋形剂处理的对照组相比，ATL-146e处理组的炎症细胞浸润显著减少，径向壁厚度降低。
在该实验模型中，用ATL-146e选择性激活腺苷2A受体可预防出血后血管痉挛并减少白细胞浸润。该药物值得进一步研究，支持炎症在蛛网膜下腔出血后脑血管痉挛发病机制中起作用这一假说。
