Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA279

Poster Communications

The role of solute carrier transporters in the translocation of the antipsychotic amisulpride at the blood-brain barrier in Alzheimer's disease and in normal ageing

S. Boyanova1, H. WANG1, S. Reeves2, S. A. Thomas1

1. King's College London, London, United Kingdom. 2. University College London, London, United Kingdom.


Alzheimer's disease (AD) patients with psychosis have an increased sensitivity to antipsychotics, such as amisulpride, and to their side effects. There is evidence that blood-brain barrier (BBB) dysfunction increases with age and with AD and that this may mediate the heightened sensitivity (Reeves et al., 2017). In order to determine the optimal dosage for AD patients, we need to further understand the transport of antipsychotics at the BBB. Previously, solute carrier transporters, such as OCT1 have been implicated in the transport of amisulpride into BBB endothelial cells (Dos Santos Pereira et al., 2014; Sekhar et al., 2018). Thus, we examined the involvement of other organic cation transporters - plasma membrane monoamine transporter (PMAT), and multi-antimicrobial extrusion proteins 1 and 2 (MATE1 and MATE2) in the transport of amisulpride at the BBB. Accumulation assays were performed in immortalized human cerebral microvessel endothelial cells/D3 (hCMEC/D3) (Sekhar et al., 2017). They were incubated with [3H]amisulpride and [14C]sucrose with or without inhibitors for PMAT, MATE1, and MATE2. Five different incubation times (5, 20, 30, 60, and 120 minutes) were used to allow accumulation of the radiolabelled solutes in the cells. The results were analysed using two-way ANOVA and GraphPad Prism Version 5 (GraphPad Software Inc., USA). All data are presented as means ± standard error. Inhibition of PMAT for 60 minutes and for 120 minutes led to a significant increase in the cellular accumulation of [3H]amisulpride by 40.9±13.2% (p=0.0306) and by 66.3±19.4% (p<0.0001), respectively (n=4, passages 30, 31 and 34). Inhibition of MATE1 for 120 minutes resulted in a significant increase in the accumulation of the radiolabelled drug in the cells by 77.7±21.1% (p<0.0001, n=3, passages 30, 31 and 34). Whereas, MATE2 inhibition for 5 and for 120 minutes resulted in a significant decrease in the cellular accumulation of [3H]amisulpride, by 36.9±14.1% (p=0.0054) and by 26.4±11.2% (p=0.0093), respectively (n=2, passages 31 and 34). PMAT, MATE1, and MATE2 may have a role in the translocation of amisulpride at the BBB. Overall, establishing the specific transporters involved in the translocation of amisulpride in good in vitro and in vivo BBB models would be valuable for improving the risk/benefit profile of existing antipsychotics and for screening of new drugs.

Where applicable, experiments conform with Society ethical requirements