Neurovascular Biology Laboratory, Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Republic of Korea.
Department of Convergence Medical Science, Brain Korea 21 Plus Program, and Institute of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
Int J Biol Macromol. 2018 Jul 15;114:1325-1337. doi: 10.1016/j.ijbiomac.2018.03.158. Epub 2018 Mar 29.
Gintonin is a ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin induces [Ca] transient and biological effects through LPA receptor and increases the permeability of the blood-brain barrier (BBB). However, little is known about its mechanisms on the BBB. We examined the in vitro effects of gintonin using primary human brain microvascular endothelial cells (HBMECs) and the in vivo effects of gintonin on brain delivery. Fluorescent-labeled gintonin bound to HBMECs and co-localized with the LPA1 receptor. Gintonin caused morphological changes, increased junctional spaces, and induced differential effects on junctional protein levels such as vascular endothelial-cadherin, occludin, zonula occludens 1, and claudin-5, in HBMECs. Gintonin led to the opening of gap junctions between HBMECs, and allowed Texas red-dextran to enter the cells, which was blocked by Ki16425, an LPA1/3 receptor antagonist, and Y27632, a Rho-associated kinase inhibitor. Intravenous administration of gintonin in rodents also increased the delivery of fluorescein isothiocyanate-dextran or erythropoietin to the brain. Furthermore, fluorescent-labeled gintonin bound to endothelial cells, neurons, and glia in the brain following its entry. Our findings show that gintonin facilitates entry to the brain through the paracellular pathway. Thus, gintonin may be an herbal medicine-derived candidate to overcome the BBB in drug delivery.
金雀异黄素是一种源自人参的 G 蛋白偶联溶血磷脂酸（LPA）受体配体。金雀异黄素通过 LPA 受体诱导 [Ca]瞬变和生物学效应，并增加血脑屏障（BBB）的通透性。然而，其对 BBB 的作用机制知之甚少。我们使用原代人脑微血管内皮细胞（HBMEC）研究了金雀异黄素的体外作用，以及金雀异黄素对脑内给药的体内作用。荧光标记的金雀异黄素与 HBMEC 结合，并与 LPA1 受体共定位。金雀异黄素引起 HBMEC 的形态变化，增加了连接间隙，并诱导连接蛋白水平的差异效应，如血管内皮钙黏蛋白、occludin、zonula occludens 1 和 claudin-5。金雀异黄素导致 HBMEC 之间的缝隙连接开放，并允许 Texas red-dextran 进入细胞，这被 LPA1/3 受体拮抗剂 Ki16425 和 Rho 相关激酶抑制剂 Y27632 阻断。在啮齿动物中静脉给予金雀异黄素也增加了荧光素异硫氰酸酯右旋糖酐或促红细胞生成素向脑内的传递。此外，进入大脑后，荧光标记的金雀异黄素与内皮细胞、神经元和神经胶质结合。我们的研究结果表明，金雀异黄素通过细胞旁途径促进进入大脑。因此，金雀异黄素可能是一种草药衍生的候选药物，可用于克服药物输送中的 BBB。
