美國科學(xué)家首次發(fā)現(xiàn)，老鼠身體內(nèi)產(chǎn)生的一種分子——腺嘌呤核苷受體能對大分子進(jìn)入大腦進(jìn)行控制,，當(dāng)腺嘌呤核苷受體在組成血腦屏障的細(xì)胞上被激活時，就會建立起一個進(jìn)入血腦屏障的通道,。相關(guān)研究發(fā)表在最新出版的《神經(jīng)科學(xué)期刊》上,。
科學(xué)家們表示，最新研究或?qū)⒔忾_“如何安全地打開和關(guān)閉血腦屏障”這個困擾科學(xué)界長達(dá)百年的謎團(tuán),，科學(xué)家們可借此更有效地治療阿爾茨海默病,、多發(fā)性硬化癥、與中央神經(jīng)系統(tǒng)有關(guān)的癌癥等,。
血腦屏障是介于血液和腦組織之間的屏障結(jié)構(gòu),，它由構(gòu)成大腦血管的特定細(xì)胞組成，其對血液中的物質(zhì)進(jìn)入大腦具有選擇性通透的作用,，能在阻止細(xì)菌的同時讓氧氣進(jìn)入大腦,，以保障腦內(nèi)環(huán)境的穩(wěn)定。然而,，血腦屏障也將藥物阻擋在外,，成為科學(xué)家治療腦神經(jīng)疾病的障礙。
100多年來,，大制藥公司一直在尋找讓藥物能突破血腦屏障來治病救人的方法,。科學(xué)家們試圖通過改變藥物使其能依附于受體和其他分子上穿越血腦屏障,，從而進(jìn)入大腦中,，但是，該修改過程會使藥物失效,。該研究的領(lǐng)導(dǎo)者,、康奈爾大學(xué)的免疫學(xué)助理教授瑪格麗特·拜努表示：“利用腺嘌呤核苷受體似乎是一個更通用的方法，利用這個機(jī)制可打開和關(guān)閉血腦屏障,。”
在實驗中,，拜努團(tuán)隊成功地將葡萄聚糖和抗體一樣大小的大分子運送至大腦中，試圖厘清它們能讓大分子到達(dá)何處以及這種方法是否對分子的大小有要求,。他們也成功地讓一個β淀粉樣肽抗體穿過轉(zhuǎn)基因老鼠的血腦屏障,，并觀察到它依附于導(dǎo)致老鼠罹患阿爾茨海默病的淀粉狀蛋白斑上,。在老鼠體內(nèi)，還有很多已知的對抗劑（專門阻止信號傳遞的藥物或者蛋白）可作腺嘌呤核苷受體,。
拜努團(tuán)隊在人體內(nèi)也發(fā)現(xiàn)了這種腺嘌呤核苷受體,。他們還發(fā)現(xiàn)，獲得美國食品藥品監(jiān)督管理局批準(zhǔn)的,、基于腺嘌呤核苷的藥物——心肌灌注造影劑Lexiscan也能輕易打開通過血腦屏障的通道,。下一步他們計劃探索遞送治療腦癌藥物的方法以及更好地理解腺嘌呤核苷受體控制血腦屏障背后的生理機(jī)制。（生物谷 Bioon.com）
doi: 10.1523/?JNEUROSCI.3337-11.2011
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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.
