BackgroundResearch into amisulpride use in Alzheimer’s disease (AD) implicates blood–brain barrier (BBB) dysfunction in antipsychotic sensitivity. Research into BBB transporters has been mainly directed towards the ABC superfamily, however, solute carrier (SLC) function in AD has not been widely studied. This study tests the hypothesis that transporters for organic cations contribute to the BBB delivery of the antipsychotics (amisulpride and haloperidol) and is disrupted in AD.MethodsThe accumulation of [3H]amisulpride (3.7–7.7 nM) and [3H]haloperidol (10 nM) in human (hCMEC/D3) and mouse (bEnd.3) brain endothelial cell lines was explored. Computational approaches examined molecular level interactions of both drugs with the SLC transporters [organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT) and multi-drug and toxic compound extrusion proteins (MATE1)] and amisulpride with the ABC transporter (P-glycoprotein). The distribution of [3H]amisulpride in wildtype and 3×transgenic AD mice was examined using in situ brain perfusion experiments. Western blots determined transporter expression in mouse and human brain capillaries .ResultsIn vitro BBB and in silico transporter studies indicated that [3H]amisulpride and [3H]haloperidol were transported by the influx transporter, OCT1, and efflux transporters MATE1 and PMAT. Amisulpride did not have a strong interaction with OCTN1, OCTN2, P-gp, BCRP or MRP and could not be described as a substrate for these transporters. Amisulpride brain uptake was increased in AD mice compared to wildtype mice, but vascular space was unaffected. There were no measurable changes in the expression of MATE1, MATE2, PMAT OCT1, OCT2, OCT3, OCTN1, OCTN2 and P-gp in capillaries isolated from whole brain homogenates from the AD mice compared to wildtype mice. Although, PMAT and MATE1 expression was reduced in capillaries obtained from specific human brain regions (i.e. putamen and caudate) from AD cases (Braak stage V–VI) compared to age matched controls (Braak stage 0–II).ConclusionsTogether our research indicates that the increased sensitivity of individuals with Alzheimer’s to amisulpride is related to previously unreported changes in function and expression of SLC transporters at the BBB (in particular PMAT and MATE1). Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for individuals with AD.

中文翻译：

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区域特异性血脑屏障转运蛋白的变化导致阿尔茨海默病患者对氨磺必利的敏感性增加


背景对氨磺必利在阿尔茨海默病（AD）中的应用的研究表明血脑屏障（BBB）功能障碍与抗精神病药物敏感性有关。 BBB转运蛋白的研究主要针对ABC超家族，然而，溶质载体（SLC）在AD中的功能尚未得到广泛研究。本研究检验了有机阳离子转运蛋白有助于抗精神病药物（氨磺必利和氟哌啶醇）的 BBB 递送并在 AD 中被破坏的假设。方法[3H]氨磺必利 (3.7–7.7 nM) 和 [3H]氟哌啶醇 (10 nM) 的积累）在人（hCMEC/D3）和小鼠（bEnd.3）脑内皮细胞系中进行了探索。计算方法检查了两种药物与 SLC 转运蛋白 [有机阳离子转运蛋白 1 (OCT1)、质膜单胺转运蛋白 (PMAT) 和多药和有毒化合物挤出蛋白 (MATE1)] 以及氨磺必利与 ABC 转运蛋白 (P -糖蛋白）。使用原位脑灌注实验检查[3H]氨磺必利在野生型和3×转基因AD小鼠中的分布。 Western blots 测定小鼠和人脑毛细血管中转运蛋白的表达。结果体外 BBB 和计算机转运蛋白研究表明[3H]氨磺必利和[3H]氟哌啶醇由流入转运蛋白 OCT1 和流出转运蛋白 MATE1 和 PMAT 转运。氨磺必利与 OCTN1、OCTN2、P-gp、BCRP 或 MRP 没有强烈的相互作用，不能被描述为这些转运蛋白的底物。与野生型小鼠相比，AD 小鼠的氨磺必利脑部摄取增加，但血管空间不受影响。 与野生型小鼠相比，从 AD 小鼠全脑匀浆分离的毛细血管中 MATE1、MATE2、PMAT OCT1、OCT2、OCT3、OCTN1、OCTN2 和 P-gp 的表达没有可测量的变化。尽管如此，与年龄匹配的对照（Braak 0-II 期）相比，从 AD 病例（Braak V-VI 期）的特定人脑区域（即壳核和尾状核）获得的毛细血管中，PMAT 和 MATE1 表达降低。结论 我们的研究共同表明，阿尔茨海默病患者对氨磺必利的敏感性增加与之前未报道的 BBB 处 SLC 转运蛋白（特别是 PMAT 和 MATE1）的功能和表达变化有关。在为 AD 患者开处方时，可能需要调整作为这些转运蛋白底物的药物的剂量。