Kastin Abba J, Akerstrom Victoria, Hackler Laszlo, Pan Weihong
VA Medical Center, New Orleans, Louisiana 70112-1262, USA.
J Neurochem. 2003 Oct;87(1):7-12. doi: 10.1046/j.1471-4159.2003.01933.x.
Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood-brain barrier (BBB) to PDGF, we examined the blood-to-brain influx of radioactively labeled PDGF isoforms (PDGF-AA and PDGF-BB) by multiple-time regression analysis after intravenous (i.v.) injection and by in-situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125I-PDGF-AA nor 125I-PDGF-BB crossed the BBB, their influx rates being similar to that of the vascular marker 99mTc-albumin. 125I-PDGF-AA degraded significantly faster in blood than 125I-PDGF-BB. PDGF-BB, however, was completely bound to a large protein in serum whereas PDGF-AA showed no binding. Thus, degradation might explain the poor blood-to-brain influx of PDGF-AA, whereas protein binding could explain the poor influx of circulating PDGF-BB. Despite their lack of permeation in the intact mouse, both 125I-PDGF-AA and 125I-PDGF-BB entered the brain by perfusion in blood-free buffer, and the significantly faster rate of 125I-PDGF-AA than 125I-PDGF-BB may be explained by the lower hydrogen bonding potential of 125I-PDGF-AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent.
血小板衍生生长因子（PDGF）对中枢神经系统具有神经营养和神经调节作用。为了确定血脑屏障（BBB）对PDGF的通透性，我们通过静脉注射（i.v.）后多次回归分析和原位灌注来检测放射性标记的PDGF异构体（PDGF-AA和PDGF-BB）从血液到脑的流入情况，并确定影响它们穿过血脑屏障的物理化学特性，包括亲脂性（通过正辛醇：缓冲液分配系数测量）、氢键（通过正辛醇：缓冲液和异辛烷：缓冲液分配系数的差异测量）、血清蛋白结合（通过毛细管电泳测量）以及静脉注射10分钟后PDGF在血液中的稳定性（通过高效液相色谱测量）。静脉推注后，125I-PDGF-AA和125I-PDGF-BB均未穿过血脑屏障，它们的流入速率与血管标记物99mTc-白蛋白相似。125I-PDGF-AA在血液中的降解速度明显快于125I-PDGF-BB。然而，PDGF-BB完全与血清中的一种大蛋白结合，而PDGF-AA未显示结合。因此，降解可能解释了PDGF-AA从血液到脑的流入不佳，而蛋白结合可以解释循环中的PDGF-BB流入不佳。尽管在完整小鼠中它们缺乏通透性，但125I-PDGF-AA和125I-PDGF-BB在无血缓冲液灌注时均进入脑内，125I-PDGF-AA比125I-PDGF-BB显著更快的速率可能由125I-PDGF-AA较低的氢键潜力来解释。因此，PDGF从血液到脑缺乏显著分布并非由于血脑屏障的内在屏障功能，而可能是由于降解和蛋白结合。这些研究的信息可能有助于设计作为治疗剂递送PDGF的类似物。
