美国科学家首次发现，老鼠身体内产生的一种分子——腺嘌呤核苷受体能对大分子进入大脑进行控制，当腺嘌呤核苷受体在组成血脑屏障的细胞上被激活时，就会建立起一个进入血脑屏障的通道。相关研究发表在最新出版的《神经科学期刊》上。
科学家们表示，最新研究或将解开“如何安全地打开和关闭血脑屏障”这个困扰科学界长达百年的谜团，科学家们可借此更有效地治疗阿尔茨海默病、多发性硬化症、与中央神经系统有关的癌症等。
血脑屏障是介于血液和脑组织之间的屏障结构，它由构成大脑血管的特定细胞组成，其对血液中的物质进入大脑具有选择性通透的作用，能在阻止细菌的同时让氧气进入大脑，以保障脑内环境的稳定。然而，血脑屏障也将药物阻挡在外，成为科学家治疗脑神经疾病的障碍。
100多年来，大制药公司一直在寻找让药物能突破血脑屏障来治病救人的方法。科学家们试图通过改变药物使其能依附于受体和其他分子上穿越血脑屏障，从而进入大脑中，但是，该修改过程会使药物失效。该研究的领导者、康奈尔大学的免疫学助理教授玛格丽特·拜努表示：“利用腺嘌呤核苷受体似乎是一个更通用的方法，利用这个机制可打开和关闭血脑屏障。”
在实验中，拜努团队成功地将葡萄聚糖和抗体一样大小的大分子运送至大脑中，试图厘清它们能让大分子到达何处以及这种方法是否对分子的大小有要求。他们也成功地让一个β淀粉样肽抗体穿过转基因老鼠的血脑屏障，并观察到它依附于导致老鼠罹患阿尔茨海默病的淀粉状蛋白斑上。在老鼠体内，还有很多已知的对抗剂（专门阻止信号传递的药物或者蛋白）可作腺嘌呤核苷受体。
拜努团队在人体内也发现了这种腺嘌呤核苷受体。他们还发现，获得美国食品药品监督管理局批准的、基于腺嘌呤核苷的药物——心肌灌注造影剂Lexiscan也能轻易打开通过血脑屏障的通道。下一步他们计划探索递送治疗脑癌药物的方法以及更好地理解腺嘌呤核苷受体控制血脑屏障背后的生理机制。（生物谷 Bioon.com）
doi: 10.1523/?JNEUROSCI.3337-11.2011
PMC:
PMID:
Adenosine Receptor Signaling Modulates Permeability of the Blood–Brain Barrier
Aaron J. Carman, Jeffrey H. Mills, Antje Krenz, Do-Geun Kim, and Margaret S. Bynoe
The blood–brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the 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 intravenously 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, intravenously 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.
