Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
J Cereb Blood Flow Metab. 2013 Dec;33(12):1944-54. doi: 10.1038/jcbfm.2013.154. Epub 2013 Sep 18.
The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.
本研究通过磁共振成像（MRI）和近红外荧光成像（NIFR），着重研究了溶血磷脂酸（LPA）对血脑屏障（BBB）通透性的影响，具体分析了 LPA 引起脑血管通透性变化的起始时间、持续时间和幅度。此外，还通过测量放射性标记的甲氨蝶呤在脑内的积累，研究了 LPA 增强药物向脑内递送的潜在应用。将 LPA 暴露于原代培养的脑微血管内皮细胞（BMEC）中，可产生浓度依赖性的通透性增加，而该增加可被梭菌毒素 B 完全消除。LPA 的给药破坏了 BBB 的完整性，并增强了小分子标志物钆二乙三胺五乙酸（Gd-DTPA）对比剂、大分子通透性标志物 IRdye800cwPEG 和 P-糖蛋白外排转运体探针 Rhodamine 800（R800）的通透性。LPA 注射后 3 分钟内 BBB 通透性增加，20 分钟内屏障完整性恢复。在重复给药后，观察到对大分子量 BBB 通透性的 LPA 反应降低。LPA 的给药还导致脑内放射性标记的甲氨蝶呤增加 20 倍。这些研究表明，LPA 与治疗剂联合给药可能会增加药物向脑内的递送。
