Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
Neurobiol Dis. 2017 Dec;108:173-182. doi: 10.1016/j.nbd.2017.08.011. Epub 2017 Aug 19.
Tissue plasminogen activator (tPA) is administered after ischemic stroke to dissolve intravascular clots, but its use can lead to hemorrhagic transformation (HT). Therapeutic strategies to reduce hemorrhagic complications of tPA might be of benefit for stroke patients. Adenosine A2b receptor (A2bR) plays pivotal roles in regulating vascular protection in peripheral organs. This study explored whether A2bR agonist BAY 60-6583 reduces hemorrhage risk after tPA usage. Using a rat transient middle cerebral artery occlusion model, we showed that mRNA and protein expression of A2bR increased to a greater extent after ischemia-reperfusion than did expression of the other three adenosine receptors (A1, A2a, and A3). tPA administration reduced A2bR expression in ischemic brain microvessels. Post-treatment with BAY 60-6583 (1mg/kg) at the start of reperfusion reduced lesion volume in the absence or presence of tPA (10mg/kg) and attenuated brain swelling, blood-brain barrier disruption, and tPA-exacerbated HT at 24h. Additionally, BAY 60-6583 mitigated sensorimotor deficits in the presence of tPA. BAY 60-6583 inhibited tPA-enhanced matrix metalloprotease-9 activation, probably through elevation of tissue inhibitor of matrix metalloproteinases-1 expression, and thereby reduced degradation of tight junction proteins. These effects would likely protect cerebrovascular integrity. A2bR agonists as an adjuvant to tPA could be a promising strategy for decreasing the risk of HT during treatment for ischemic stroke.
组织型纤溶酶原激活物（tPA）在缺血性中风后用于溶解血管内的血栓，但它的使用可能会导致出血性转化（HT）。减少 tPA 引起的出血并发症的治疗策略可能对中风患者有益。腺苷 A2b 受体（A2bR）在调节外周器官的血管保护中起着关键作用。本研究探讨了 A2bR 激动剂 BAY 60-6583 是否能降低 tPA 使用后的出血风险。使用大鼠短暂性大脑中动脉闭塞模型，我们发现 A2bR 的 mRNA 和蛋白表达在缺血再灌注后比其他三种腺苷受体（A1、A2a 和 A3）增加得更明显。tPA 给药降低了缺血性脑微血管中的 A2bR 表达。在再灌注开始时用 BAY 60-6583（1mg/kg）进行后处理，在没有或存在 tPA（10mg/kg）的情况下减少了病变体积，并减轻了脑水肿、血脑屏障破坏以及 tPA 加重的 HT 在 24 小时时的情况。此外，BAY 60-6583 在存在 tPA 的情况下减轻了感觉运动缺陷。BAY 60-6583 抑制了 tPA 增强的基质金属蛋白酶-9 的激活，可能是通过提高组织抑制剂的表达来实现的，从而减少了紧密连接蛋白的降解。这些作用可能有助于保护脑血管的完整性。作为 tPA 的辅助剂的 A2bR 激动剂可能是降低缺血性中风治疗期间 HT 风险的一种有前途的策略。
