King's College London, Institute of Pharmaceutical Science, London, United Kingdom.
King's College London, Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, London, United Kingdom.
PLoS One. 2023 Oct 24;18(10):e0286278. doi: 10.1371/journal.pone.0286278. eCollection 2023.
Blood-brain barrier (BBB) dysfunction may be involved in the increased sensitivity of Alzheimer's disease (AD) patients to antipsychotics, including amisulpride. Studies indicate that antipsychotics interact with facilitated glucose transporters (GLUT), including GLUT1, and that GLUT1 BBB expression decreases in AD. We tested the hypotheses that amisulpride (charge: +1) interacts with GLUT1, and that BBB transport of amisulpride is compromised in AD. GLUT1 substrates, GLUT1 inhibitors and GLUT-interacting antipsychotics were identified by literature review and their physicochemical characteristics summarised. Interactions between amisulpride and GLUT1 were studied using in silico approaches and the human cerebral endothelial cell line, hCMEC/D3. Brain distribution of [3H]amisulpride was determined using in situ perfusion in wild type (WT) and 5xFamilial AD (5xFAD) mice. With transmission electron microscopy (TEM) we investigated brain capillary degeneration in WT mice, 5xFAD mice and human samples. Western blots determined BBB transporter expression in mouse and human. Literature review revealed that, although D-glucose has no charge, charged molecules can interact with GLUT1. GLUT1 substrates are smaller (184.95±6.45g/mol) than inhibitors (325.50±14.40g/mol) and GLUT-interacting antipsychotics (369.38±16.04). Molecular docking showed beta-D-glucose (free energy binding: -15.39kcal/mol) and amisulpride (-29.04kcal/mol) interact with GLUT1. Amisulpride did not affect [14C]D-glucose hCMEC/D3 accumulation. [3H]amisulpride uptake into the brain (except supernatant) of 5xFAD mice compared to WT remained unchanged. TEM revealed brain capillary degeneration in human AD. There was no difference in GLUT1 or P-glycoprotein BBB expression between WT and 5xFAD mice. In contrast, caudate P-glycoprotein, but not GLUT1, expression was decreased in human AD capillaries versus controls. This study provides new details about the BBB transport of amisulpride, evidence that amisulpride interacts with GLUT1 and that BBB transporter expression is altered in AD. This suggests that antipsychotics could potentially exacerbate the cerebral hypometabolism in AD. Further research into the mechanism of amisulpride transport by GLUT1 is important for improving antipsychotics safety.
血脑屏障 (BBB) 功能障碍可能与阿尔茨海默病 (AD) 患者对包括氨磺必利在内的抗精神病药物的敏感性增加有关。研究表明，抗精神病药物与易化葡萄糖转运体 (GLUT) 相互作用，包括 GLUT1，而 AD 中 GLUT1 的 BBB 表达减少。我们检验了以下假设：氨磺必利 (电荷：+1) 与 GLUT1 相互作用，并且 AD 中氨磺必利的 BBB 转运受损。通过文献回顾确定了 GLUT1 底物、GLUT1 抑制剂和与 GLUT 相互作用的抗精神病药物，并总结了它们的理化特性。使用计算机模拟方法和人脑血管内皮细胞系 hCMEC/D3 研究了氨磺必利与 GLUT1 之间的相互作用。使用原位灌流在野生型 (WT) 和 5xFamilial AD (5xFAD) 小鼠中确定了 [3H]氨磺必利的脑分布。通过透射电子显微镜 (TEM) 研究了 WT 小鼠、5xFAD 小鼠和人类样本中的脑毛细血管退化。Western blot 确定了小鼠和人类 BBB 转运体的表达。文献综述表明，尽管 D-葡萄糖没有电荷，但带电分子可以与 GLUT1 相互作用。GLUT1 底物比抑制剂 (325.50±14.40g/mol) 和与 GLUT 相互作用的抗精神病药物 (369.38±16.04) 更小。分子对接表明 β-D-葡萄糖 (自由能结合：-15.39kcal/mol) 和氨磺必利 (-29.04kcal/mol) 与 GLUT1 相互作用。氨磺必利不影响 hCMEC/D3 对 [14C]D-葡萄糖的积累。与 WT 相比，5xFAD 小鼠脑内 [3H]氨磺必利摄取（除上清液外）保持不变。TEM 显示人类 AD 中的脑毛细血管退化。WT 和 5xFAD 小鼠之间 GLUT1 或 P-糖蛋白 BBB 表达无差异。相比之下，与对照组相比，人类 AD 毛细血管中的尾状核 P-糖蛋白表达减少，而 GLUT1 表达无差异。本研究提供了关于氨磺必利 BBB 转运的新细节，表明氨磺必利与 GLUT1 相互作用，AD 中 BBB 转运体的表达发生改变。这表明抗精神病药物可能会加重 AD 中的大脑低代谢。进一步研究 GLUT1 转运氨磺必利的机制对于提高抗精神病药物的安全性很重要。
