Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Neurosurg. 2010 Oct;113(4):826-34. doi: 10.3171/2009.9.JNS09802.
The role of adenosine A(2A) receptors in the early vascular response after subarachnoid hemorrhage (SAH) is unknown. In other forms of cerebral ischemia both activation and inhibition of A(2A) receptors is reported to be beneficial. However, these studies mainly used pharmacological receptor modulation, and most of the agents available exhibit low specificity. The authors used adenosine A(2A) receptor knockout mice to study the role of A(2A) receptors in the early vascular response to SAH.
Subarachnoid hemorrhage was induced in wild-type mice (C57BL/6) and A(2A) receptor knockout mice by endovascular puncture. Cerebral blood flow, intracranial pressure, and blood pressure were recorded, and cerebral perfusion pressure was deduced. Animals were sacrificed at 1, 3, or 6 hours after SAH or sham surgery. Coronal brain sections were immunostained for Type IV collagen, the major protein of the basal lamina. The internal diameter of major cerebral arteries and the area fraction of Type IV collagen-positive microvessels (< 100 μm) were determined.
The initial increase in intracranial pressure and decrease in cerebral perfusion pressure at SAH induction was similar in both types of mice, but cerebral blood flow decline was significantly smaller in A(2A) receptor knockout mice as compared with wild-type cohorts. The internal diameter of major cerebral vessels decreased progressively after SAH. The extent of diameter reduction was significantly less in A(2A) receptor knockout mice than in wild-type mice. Type IV collagen immunostaining decreased progressively after SAH. This decrease was significantly less in A(2A) receptor knockout mice than in wild-type mice.
These results demonstrate that global inactivation of A(2A) receptors decreases the intensity of the early vascular response to SAH. Early inhibition of A(2A) receptors after SAH might reduce cerebral injury.
腺苷 A(2A) 受体在蛛网膜下腔出血 (SAH) 后的早期血管反应中的作用尚不清楚。在其他形式的脑缺血中，A(2A) 受体的激活和抑制均被报道是有益的。然而，这些研究主要使用药理学受体调节，并且大多数可用的药物表现出低特异性。作者使用腺苷 A(2A) 受体敲除小鼠来研究 A(2A) 受体在 SAH 后早期血管反应中的作用。
通过血管内穿刺在野生型小鼠 (C57BL/6) 和 A(2A) 受体敲除小鼠中诱导蛛网膜下腔出血。记录脑血流、颅内压和血压，并推断脑灌注压。在 SAH 或假手术后 1、3 或 6 小时处死动物。对冠状脑切片进行 IV 型胶原免疫染色，IV 型胶原是基底层的主要蛋白。测量主要脑血管的内径和 IV 型胶原阳性微血管 (＜100 μm) 的面积分数。
SAH 诱导时颅内压的初始升高和脑灌注压的降低在两种类型的小鼠中相似，但与野生型小鼠相比，A(2A) 受体敲除小鼠的脑血流下降明显较小。SAH 后主要脑血管的内径逐渐减小。A(2A) 受体敲除小鼠的直径减小程度明显小于野生型小鼠。SAH 后 IV 型胶原免疫染色逐渐减少。与野生型小鼠相比，A(2A) 受体敲除小鼠的减少程度明显较小。
这些结果表明，A(2A) 受体的全局失活可降低 SAH 后早期血管反应的强度。SAH 后早期抑制 A(2A) 受体可能减少脑损伤。
