High transcytosis of melanotransferrin (P97) across the blood brain barrier
High transcytosis of melanotransferrin (P97) across the blood brain barrier
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DOI：
10.1046/j.1471-4159.2002.01201.x
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发表时间：
2002-11-01
影响因子：
4.7
通讯作者：
Béliveau, R
中科院分区：
文献类型：
--
作者：
Demeule, M;Poirier, J;Béliveau, R
血脑屏障（BBB）通过严格控制进入大脑来执行神经保护功能;因此，它也阻碍蛋白质以及药理学试剂进入脑组织。我们在这里证明，重组人黑素转铁蛋白（P97）是高度积累到小鼠脑静脉注射和原位脑灌注后。此外，P97跨牛脑毛细血管内皮细胞（BBCEC）单层的转胞吞作用比全转铁蛋白高至少14倍，没有明显的内皮内降解。P97的这种高转胞吞作用与BBCEC单层完整性的变化无关。此外，P97的跨内皮转运对温度敏感，并且具有浓度和构象依赖性，表明P97的转运是由于受体介导的内吞作用。尽管P97和转铁蛋白之间的高度序列同一性，但与转铁蛋白不同的受体参与P97的跨内皮转运。低密度脂蛋白受体蛋白家族的一个成员，可能是LRP，似乎参与P97跨内皮转运。脑蓄积、P97转胞吞的高速率及其在血液中的非常低的水平表明，P97可以有利地用作新的递送系统以将药物直接靶向至脑。
The blood-brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of proteins as well as pharmacological agents to cerebral tissues. We demonstrate here that recombinant human melanotransferrin (P97) is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14-fold higher than that of holo-transferrin, with no apparent intra-endothelial degradation. This high transcytosis of P97 was not related to changes in the BBCEC monolayer integrity. In addition, the transendothelial transport of P97 was sensitive to temperature and was both concentration- and conformation-dependent, suggesting that the transport of P97 is due to receptor-mediated endocytosis. In spite of the high degree of sequence identity between P97 and transferrin, a different receptor than the one for transferrin is involved in P97 transendothelial transport. A member of the low-density lipoprotein receptor protein family, likely LRP, seems to be involved in P97 transendothelial transport. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be advantageously employed as a new delivery system to target drugs directly to the brain.