Heightened sensitivity of people with Alzheimer’s disease to the side effects of antipsychotic drug amisulpride may be mediated through an interaction with glucose transporter 1 at the blood‐brain barrier

Abstract

Background Amisulpride is an atypical antipsychotic which antagonises dopamine (D2, D3) receptors in vitro and in vivo (Schoemaker et al., 1997). Older people, particularly those with dementia are more susceptible to antipsychotic side effects, including amisulpride (Reeves et al., 2017). Clinical and basic science research suggested that blood‐brain barrier (BBB) disruption underpins this heightened sensitivity by increasing central drug access (Sekhar et al., 2019; Harwood et al., 1994). The current study examines healthy and Alzheimer’s disease (AD) physiology to further understand this increased sensitivity. Method We investigated the BBB transport of amisulpride in 5xFamilial Alzheimer’s mouse model (5xFAD), and in age‐matched wild type mice (WT, C57/BL6) (12‐15 months old). 5xFAD mice express human amyloid precursor protein and presenilin 1 transgenes with five AD‐linked mutations, they develop Aβ plaques and cognitive impairments (Oakley et al., 2006). All experiments were performed according the Animal Scientific Procedures Act (1986) and Amendment Regulations 2012. Anaesthesia was applied via intraperitoneal injection of medetomidine hydrochloride and ketamine mixture. The mice were perfused with artificial plasma, containing [3H]amisulpride (6.5 nM) and [14C]sucrose (9.4 μM). Brain amyloid plaques were confirmed in 5xFAD mice by transmission electron microscopy. In silico molecular docking using AuDock Vina and GOLD software identified transporters of interest for our model substrate. Amisulpride was considered a substrate for a given transporter, if it had free energy binding lower than ‐5 kcal/mole and high chem score. Result Compared to WT (n=6), the 5xFAD (n=7) mice had increased striatal [3H]amisulpride uptake of 79% (t=1.975, df=11, p=0.0370). The [14C]sucrose (passive permeability measure) permeability was not significantly changed. Preliminary in silico analysis suggested that amisulpride is a substrate for glucose transporter 1 (GLUT1) and a very weak substrate for multidrug and toxin extrusion transporter (MATE2) (Table 1). Conclusion In silico studies suggested amisulpride interacts with BBB solute carrier (SLC) transporters: organic cation transporter (OCT1), plasma membrane monoamine transporter (PMAT), MATE1 (Sekhar et al., 2019), GLUT1 and MATE2, but not with the adenosine triphosphate binding cassette (ABC) transporter P‐glycoprotein. The increased brain permeability to amisulpride in 5xFAD mice suggests altered BBB transporter function, possibly due to SLC transporter expression changes associated with AD.

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

“…An overview of the methods deployed are presented in S1 Fig in S1 File . Abstracts of this work have been presented [ 26 ].…”