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Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer’s disease

Boyanova, Sevda T; Lloyd-Morris, Ethlyn; Corpe, Christopher; Rahman, Khondaker Miraz; Farag, Doaa B; Page, Lee K; Wang, Hao; ... Thomas, Sarah A; + view all (2023) Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer’s disease. PLoS One , 18 (10) , Article e0286278. 10.1371/journal.pone.0286278. Green open access

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Abstract

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.

Type: Article
Title: Interaction of amisulpride with GLUT1 at the blood-brain barrier. Relevance to Alzheimer’s disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0286278
Publisher version: https://doi.org/10.1371/journal.pone.0286278
Language: English
Additional information: Copyright: © 2023 Boyanova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Humans, Mice, Animals, Blood-Brain Barrier, Amisulpride, Alzheimer Disease, Glucose Transporter Type 1, Molecular Docking Simulation, Brain, Membrane Transport Proteins, Antipsychotic Agents, Glucose, Glucose Transport Proteins, Facilitative, ATP Binding Cassette Transporter, Subfamily B
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health of Older People
URI: https://discovery.ucl.ac.uk/id/eprint/10180201
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