Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

Gayathri Nair Sekhar; Alice L. Fleckney; Sevda Tomova Boyanova; Huzefa Rupawala; Rachel Lo; Hao Wang; Doaa Boshra Farag; Khondaker Miraz Rahman; Martin Broadstock; Suzanne Reeves; Sarah Ann Thomas

doi:10.1186/s12987-019-0158-1

NeuroscienceFluids and Barriers of the CNSDec 1, 2019

Peer-reviewed journal article

Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

Gayathri Nair Sekhar iD, Alice L. Fleckney, Sevda Tomova Boyanova iD, Huzefa Rupawala iD, Rachel Lo iD, Hao Wang iD, Doaa Boshra Farag iD, Khondaker Miraz Rahman iD, Martin Broadstock, Suzanne Reeves iD, Sarah Ann Thomas iD

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Abstract

Research into amisulpride use in Alzheimers disease (AD) implicates blood-brain barrier (BBB) dysfunction in antipsychotic sensitivity. Solute carrier function in AD has not been widely studied. This study tests the hypothesis that organic cation transporters contribute to the BBB delivery of antipsychotics and is disrupted in AD.\n\nIn vitro BBB studies indicated that [3H]amisulpride and [3H]haloperidol were transported by OCT1. Amisulpride also utilized PMAT. Molecular docking predicted that amisulpride and haloperidol are OCT1, PMAT and MATE1 substrates, and amisulpride is not a P-gp substrate. Amisulpride brain uptake increased in 3xTgAD compared to wildtype mice. PMAT and MATE1 expression was reduced in brain from AD patients compared to controls. The increased sensitivity of Alzheimers patients to amisulpride is related to previously unreported changes in OCT1, PMAT and MATE1 function/expression at the BBB. Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for AD patients.