Adenosine receptor signaling modulates permeability of the blood-brain barrier.
Adenosine receptor signaling modulates permeability of the blood-brain barrier.
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DOI：
10.1523/jneurosci.3337-11.2011
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发表时间：
2011-09-14
期刊：
影响因子：
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通讯作者：
Bynoe MS
中科院分区：
文献类型：
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作者：
Carman AJ;Mills JH;Krenz A;Kim DG;Bynoe MS
血脑屏障 (BBB) 由专门的内皮细胞组成，形成中枢神经系统 (CNS) 的毛细血管微血管系统，对大脑功能至关重要。它还对许多中枢神经系统疾病的治疗造成最大障碍，因为它通常会阻止治疗化合物的进入。在这里，我们报告腺苷受体 (AR) 信号传导调节体内 BBB 通透性。 A1 和 A2A AR 激活促进静脉注射的大分子（包括大葡聚糖和 β-淀粉样蛋白抗体）进入小鼠大脑。此外，使用 FDA 批准的选择性 A2A 激动剂 Lexiscan 进行治疗也可以增加小鼠模型中的 BBB 通透性。 BBB 通透性的这些变化是剂量依赖性的并且在时间上是离散的。缺乏 A1 或 A2A AR 的转基因小鼠在 AR 激动后表现出右旋糖酐进入大脑的减少。在用广谱 AR 激动剂治疗后，在阿尔茨海默病 (AD) 转基因小鼠模型中，观察到静脉注射的抗 β-淀粉样蛋白抗体进入中枢神经系统并与 β-淀粉样蛋白斑块结合。选择性 AR 激活导致体外细胞变化，包括跨内皮电阻降低、放线肌球蛋白应力纤维形成增加以及紧密连接分子的改变。这些结果表明 AR 信号传导可用于调节体内 BBB 通透性，以促进潜在治疗化合物进入 CNS。脑内皮细胞的 AR 信号传导代表了一种调节 BBB 通透性的新内源性机制。我们预计这些结果将有助于 AD、帕金森病、多发性硬化症和中枢神经系统癌症等神经系统疾病的药物设计、药物输送和治疗选择。
The blood-brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the central nervous system (CNS) and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A1 and A2A AR activation facilitated the entry of i.v.-administered macromolecules, including large dextrans and antibodies to β-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A2A agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A1 or A2A ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad spectrum AR agonist, i.v.-administered anti-β-amyloid antibody was observed to enter the CNS and bind β-amyloid plaques in a transgenic mouse model of Alzheimer’s disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson’s disease, multiple sclerosis and cancers of the CNS.