Poduslo J F, Curran G L
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Brain Res Mol Brain Res. 1996 Mar;36(2):280-6. doi: 10.1016/0169-328x(95)00250-v.
A comparison was made of the permeabilities of different neurotrophic factors at the blood-brain barrier (BBB) and blood-nerve barrier (BNB) in normal adult rats by quantifying the permeability coefficient-surface area (PS) product after correction for the residual plasma volume (Vp) occupied by the protein in the capillary bed of the nerve endoneurium or different brain regions. The i.v. bolus injection technique was used in the cannulated brachial vein and artery using the same protein radioiodinated with a second isotope of iodine (125I vs. 131I) to separately determine the PS and Vp values. The plasma washout showed a decreasing plasma half-life in the order of brain-derived neurotrophic factor (BDNF) < neurotrophin-3 (NT-3) < ciliary neurotrophic factor (CNTF) < nerve growth factor (NGF). The PS at the BNB for NGF was 1.40 +/- 0.15 x 10(-6) ml/g/s (mean +/- SEM). The other neurotrophic proteins were all significantly higher than NGF (CNTF: 9.5 x ; NT-3: 20.8 x ; BDNF: 18.9 x ). The Vp for NGF at the BNB was 1.92 +/- 0.12 microliters/g and was not significantly different from the other proteins except for NGF vs. BDNF (P < 0.05). The PS for NGF at the BBB ranged from 1.5 to 2.7 x 10(-6) ml/g/s for six different brain regions. The PS for CNTF ranged from 6.0 to 8.0-fold higher than NGF; NT-3: 10.6 to 15.2-fold higher; and BDNF: 11.3 to 16.4-fold higher. The Vp values were not significantly different except for CNTF in the hippocampus and cortex (P < 0.05). SDS-PAGE analyses of all the radioiodinated neurotrophic proteins after 60 min of uptake revealed intact protein in the endoneurium and in the six different brain regions with exposure times of 2-42 days. The quantification of the permeability of these neurotrophic proteins provides baseline values for comparison of different protein modifications that enhance the PS while still preserving the neurotrophic activity (e.g., protein glycation; Poduslo and Curran, Mol. Brain Res., 23 (1994) 157). Enhanced permeability following modification might allow the use of systematic delivery of these proteins for practical therapeutic treatment of various neurodegenerative disorders.
通过校正神经内膜或不同脑区毛细血管床中蛋白质所占的残余血浆体积（Vp）后，对正常成年大鼠血脑屏障（BBB）和血神经屏障（BNB）处不同神经营养因子的通透性进行了比较，方法是量化通透系数-表面积（PS）乘积。采用静脉推注技术，在插管的肱静脉和动脉中使用用第二种碘同位素（125I与131I）放射性碘化的相同蛋白质，分别测定PS和Vp值。血浆清除显示，血浆半衰期按脑源性神经营养因子（BDNF）<神经营养素-3（NT-3）<睫状神经营养因子（CNTF）<神经生长因子（NGF）的顺序递减。NGF在BNB处的PS为1.40±0.15×10-6 ml/g/s（平均值±标准误）。其他神经营养蛋白均显著高于NGF（CNTF：9.5倍；NT-3：20.8倍；BDNF：18.9倍）。NGF在BNB处的Vp为1.92±0.12微升/g，除NGF与BDNF相比（P<0.05）外，与其他蛋白质无显著差异。在六个不同脑区，NGF在BBB处的PS范围为1.5至2.7×10-6 ml/g/s。CNTF的PS比NGF高6.0至8.0倍；NT-3：高10.6至15.2倍；BDNF：高11.3至16.4倍。除海马体和皮质中的CNTF外，Vp值无显著差异（P<0.05）。摄取60分钟后，对所有放射性碘化神经营养蛋白进行的SDS-PAGE分析显示，在神经内膜和六个不同脑区有完整的蛋白质，曝光时间为2至42天。这些神经营养蛋白通透性的量化为比较不同蛋白质修饰提供了基线值，这些修饰可提高PS，同时仍保留神经营养活性（例如蛋白质糖基化；Poduslo和Curran，《分子脑研究》，23（1994）157）。修饰后通透性增强可能允许通过系统给药这些蛋白质来实际治疗各种神经退行性疾病。
