Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier
Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier
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DOI：
10.1016/j.expneurol.2004.09.013
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发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
Banks, WA
中科院分区：
文献类型：
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作者：
Nonaka, N;Shioda, S;Banks, WA
垂体腺苷酸环化酶激活多肽 (PACAP) 具有针对缺血的神经保护作用，即使在中风后 24 小时通过静脉 (iv) 给药也是如此。 PACAP 通过肽转运系统 (PTS)-6 穿过血脑屏障 (BBB) 的转运是其静脉注射后有效的基础。然而，PACAP 转运在中枢神经系统 (CNS) 损伤后发生改变，引发了细胞因子或 BBB 破坏是否影响 PTS-6 活性的问题。脂多糖 (LPS) 源自细菌细胞壁，通过释放细胞因子和破坏 BBB 来影响其他蛋白质穿过 BBB。在这里，我们通过多种方法检查了腹膜内 (ip) 注射 LPS 后放射性标记的 PACAP (I-PACAP) 穿过 BBB 的转运情况。在注射三剂 LPS 后，单个时间点的研究发现 LPS 对 I-PACAP 和放射性标记白蛋白 (I-Albumin) 的大脑/血清比率有不同的影响。 LPS 增加了 I-白蛋白的比率，表明 BBB 受到破坏，但它却降低了 I-PACAP 的比率。多次回归分析、毛细血管耗竭和脑灌注表明，这种减少完全可以通过 I-PACAP 与脑内皮的初始可逆结合的减少来解释，而 PACAP 转运到大脑中的速率没有改变。这些方法还表明，LPS 处理的小鼠体积收缩。这种体积收缩浓缩了血液中 I-PACA-P 的量，因此增加了呈递至 BBB 的 I-PACAP 量。运输速率没有变化加上体积收缩导致进入大脑的 I-PACAP 静脉注射剂量净增加约 30%。 LPS 不会改变 I-PACAP 从 CNS 的流出。总之，PTS-6 保持活性，并且应该能够在涉及细胞因子释放和 BBB 破坏的脑损伤中向 CNS 输送治疗量的 PACAP。 (C) 2004 Elsevier Inc. 保留所有权利。
Pituitary adenylate cyclase activating polypeptide (PACAP) has neuroprotective effects against ischemia, even when given by intravenous (iv) administration 24 h after stroke. Transport of PACAP across the blood-brain barrier (BBB) by peptide transport system (PTS)-6 underlies its effectiveness after iv administration. However, PACAP transport is modified after central nervous system (CNS) injury, raising the question of whether cytokines or BBB disruption affects PTS-6 activity. Lipopolysaccharide (LPS) is derived from bacterial cell walls and affects the passage of other proteins across the BBB through its release of cytokines and disruption of the BBB. Here, we examined by several methods the transport of radioactively labeled PACAP (I-PACAP) across the BBB after intraperitoneal (ip) injection of LPS. After three doses of LPS, studies at a single time point found a differential effect of LPS on the brain/serum ratio for I-PACAP and radioactively labeled albumin (I-Albumin). Whereas LPS increased the ratio for I-Albumin, demonstrating BBB disruption, it decreased the ratio for I-PACAP. Multiple-time regression analysis, capillary depletion, and brain perfusion showed that this decrease was fully explained by a decrease in the initial, reversible binding of I-PACAP to brain endothelium, while the rate of transport of PACAP into the brain was not altered. These methods also showed that the LPS-treated mice were volume contracted. This volume contraction concentrated the amount of I-PACA-P in the blood and so increased the amount of I-PACAP presented to the BBB. Lack of change in transport rate combined with volume contraction resulted in a net increase of about 30% of the iv dose of I-PACAP entering the brain. LPS did not alter the efflux of I-PACAP from the CNS. In conclusion, PTS-6 remains active and should be able to deliver therapeutic amounts of PACAP to the CNS in brain injuries involving cytokine release and BBB disruption. (C) 2004 Elsevier Inc. All rights reserved.