Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6.
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada T6G 2E9.
Aquat Toxicol. 2014 Jan;146:176-85. doi: 10.1016/j.aquatox.2013.10.035. Epub 2013 Nov 7.
The importance of the blood brain barrier (BBB) and the contribution to its function by the efflux transporter P-glycoprotein (P-gp) in teleosts were examined using the P-gp substrates and central nervous system neurotoxins ivermectin (22,23-dihydroavermectin B1a+22,23-dihydroavermectin B1b) [IVM]) and emamectin benzoate (4″-deoxy-49″epimethylaminoavermectin B1 benzoate [EB]). Trout were injected intraperitoneally with 0.01-1.0 and 1-50mg/kg of IVM or EB, respectively either alone or in combination with cyclosporin A (CsA: a P-gp substrate) at 1mg/kg. IVM affected the swimming performance (critical swimming speed, burst swimming distance, and schooling) at significantly lower concentrations than EB. When fish were exposed to IVM or EB in the presence of CsA, alterations to swimming were increased, suggesting that competition for P-gp in the BBB by CsA increased IVM and EB penetration into the CNS and decreased swimming capabilities. The effect of co-administration of CsA on swimming-related toxicity was different between IVM and EB-treated fish; EB toxicity was increased to a greater extent than IVM toxicity. The greater chemosensitization effect of EB vs. IVM was examined using a P-gp competitive inhibition assay in isolated trout hepatocytes with rhodamine 123 as a substrate. At the cellular level, IVM was a more potent inhibitor of P-gp than EB, which allowed for a greater accumulation of R123 in hepatocytes. These results provide evidence for a role of P-gp in the BBB of fish, and suggest that this protein protects fish from environmental neurotoxins.
血脑屏障（BBB）的重要性及其在鱼类中流出转运蛋白 P-糖蛋白（P-gp）对其功能的贡献，使用 P-gp 底物和中枢神经系统神经毒素伊维菌素（22,23-二氢阿维菌素 B1a+22,23-二氢阿维菌素 B1b）[IVM]）和依维菌素苯甲酸盐（4″-脱氧-49″-表甲氨基阿维菌素 B1 苯甲酸盐[EB]）进行了检查。分别向鳟鱼腹膜内注射 0.01-1.0 和 1-50mg/kg 的 IVM 或 EB，单独或与环孢素 A（CsA：P-gp 底物）一起以 1mg/kg 注射。IVM 以比 EB 低得多的浓度影响游泳性能（临界游泳速度、爆发游泳距离和集群）。当鱼在 CsA 存在下暴露于 IVM 或 EB 时，游泳的变化增加，这表明 CsA 在 BBB 中与 P-gp 的竞争增加了 IVM 和 EB 穿透中枢神经系统的能力，并降低了游泳能力。CsA 对游泳相关毒性的共同给药的影响在 IVM 和 EB 处理的鱼类之间不同；EB 毒性比 IVM 毒性增加得更大。使用 rhodamine 123 作为底物的分离鳟鱼肝细胞中的 P-gp 竞争性抑制测定，检查了 EB 与 IVM 的化学增敏作用的差异。在细胞水平上，IVM 是比 EB 更强的 P-gp 抑制剂，这使得 R123 在肝细胞中积累更多。这些结果为鱼类 BBB 中 P-gp 的作用提供了证据，并表明该蛋白保护鱼类免受环境神经毒素的侵害。
