Youdim Kuresh A, Qaiser M Zeeshan, Begley David J, Rice-Evans Catherine A, Abbott N Joan
Antioxidant Research Group, Wolfson Centre for Age-Related Diseases, Centre for Neuroscience Research, Guy's King's and St Thomas's School of Biomedical Sciences, King's College, London SE1 1UL, UK.
Free Radic Biol Med. 2004 Mar 1;36(5):592-604. doi: 10.1016/j.freeradbiomed.2003.11.023.
Understanding mechanisms associated with flavonoid neuroprotection is complicated by the lack of information on their ability to enter the CNS. This study examined naringenin and quercetin permeability across the blood-brain barrier (BBB), using in vitro (ECV304/C6 coculture) and in situ (rat) models. We report measurable permeabilities (P(app)) for both flavonoids across the in vitro BBB model, consistent with their lipophilicity. Both flavonoids showed measurable in situ BBB permeability. The rates of uptake (K(in)) into the right cerebral hemisphere were 0.145 and 0.019 ml min(-1) g(-1) for naringenin and quercetin, respectively. Quercetin K(in) was comparable to that of colchicine (0.006 ml min(-1) g(-1)), a substrate for P-glycoprotein (P-gp). Preadministration of the P-gp inhibitor PSC833 or GF120918 (10 mg/kg body wt) significantly increased colchicine K(in), but only GF120918 (able to inhibit breast cancer resistance protein, BCRP) affected K(in) for quercetin. Naringenin K(in) was not affected. The influence of efflux transporters on flavonoid permeability at the BBB was further studied using MDCK-MDR1 and immortalized rat brain endothelial cells (RBE4). Colchicine, quercetin, and naringenin all showed measurable accumulation (distribution volume, V(d) (microl/mg protein)) in both cell types. The V(d) for colchicine increased significantly in both cell lines following coincubation with either PSC833 (25 microM) or GF120918 (25 microM). Both inhibitors also caused an increase in naringenin V(d); by contrast only GF120918 coincubation significantly increased quercetin V(d). In conclusion, the results demonstrate that flavonoids are able to traverse the BBB in vivo. However, the permeability of certain flavonoids in vivo is influenced by their lipophilicity and interactions with efflux transporters.
由于缺乏关于类黄酮进入中枢神经系统能力的信息，了解其神经保护相关机制变得复杂。本研究使用体外（ECV304/C6共培养）和原位（大鼠）模型，检测了柚皮素和槲皮素穿过血脑屏障（BBB）的通透性。我们报告了两种类黄酮在体外BBB模型中的可测量通透性（P(app)），这与其亲脂性一致。两种类黄酮在原位BBB中均显示出可测量的通透性。柚皮素和槲皮素进入右大脑半球的摄取速率（K(in)）分别为0.145和0.019 ml min(-1) g(-1)。槲皮素的K(in)与秋水仙碱（0.006 ml min(-1) g(-1)）相当，秋水仙碱是P-糖蛋白（P-gp）的底物。预先给予P-gp抑制剂PSC833或GF120918（10 mg/kg体重）可显著增加秋水仙碱的K(in)，但只有GF120918（能够抑制乳腺癌耐药蛋白，BCRP）影响槲皮素的K(in)。柚皮素的K(in)不受影响。使用MDCK-MDR1和永生化大鼠脑内皮细胞（RBE4）进一步研究了外排转运体对BBB处类黄酮通透性的影响。秋水仙碱、槲皮素和柚皮素在两种细胞类型中均显示出可测量的蓄积（分布体积，V(d)（微升/毫克蛋白））。与PSC833（25 microM）或GF120918（25 microM）共同孵育后，两种细胞系中秋水仙碱的V(d)均显著增加。两种抑制剂也导致柚皮素V(d)增加；相比之下，只有与GF120918共同孵育显著增加了槲皮素的V(d)。总之，结果表明类黄酮能够在体内穿过BBB。然而，某些类黄酮在体内的通透性受其亲脂性以及与外排转运体相互作用的影响。
