Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier
Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier
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DOI：
10.1038/jcbfm.2013.160
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发表时间：
2013-12-01
影响因子：
6.3
通讯作者：
Calon, Frederic
中科院分区：
文献类型：
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作者：
St-Amour, Isabelle;Pare, Isabelle;Calon, Frederic
静脉注射免疫球蛋白(IVIg)目前正在进行临床试验，用于治疗各种中枢神经系统疾病。为了评估其达到中心治疗目标的能力，必须确定IVIg的脑生物利用度。因此，我们使用互补的定量和定性方法对IVIg通过C57BI/6小鼠的血脑屏障(BBB)的能力进行了量化。用酶联免疫吸附试验检测到小鼠脑内注射IVIg的比例很小(注射剂量的0.009+/-0.001%在皮质)，而免疫染色显示主要定位于微血管内，较少见于神经元。药代动力学分析表明，阿昔洛韦在大脑皮层的消除速率常数较低(每小时0.0053)，与脑组织内的蓄积一致。原位脑灌注实验显示，部分IVIg穿过血脑屏障，没有引起渗漏。脑摄取的剂量依赖性下降符合饱和的血到脑运输机制。最后，在阿尔茨海默病3xTg-AD小鼠模型中，亚慢性治疗后大脑对IVIg的摄取与非转基因对照组相似。综上所述，我们的结果提供了血脑屏障通过和IVIg生物利用度的证据，在没有血脑屏障渗漏和足够的浓度与治疗靶点相互作用的情况下。
Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57BI/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009 +/- 0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053 per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.