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

Abstract

BackgroundResearch into amisulpride use in Alzheimer’s disease (AD) implicates blood–brain barrier (BBB) dysfunction in antipsychotic sensitivity. Research into BBB transporters has been mainly directed towards the ABC superfamily, however, solute carrier (SLC) function in AD has not been widely studied. This study tests the hypothesis that transporters for organic cations contribute to the BBB delivery of the antipsychotics (amisulpride and haloperidol) and is disrupted in AD.MethodsThe accumulation of [3H]amisulpride (3.7–7.7 nM) and [3H]haloperidol (10 nM) in human (hCMEC/D3) and mouse (bEnd.3) brain endothelial cell lines was explored. Computational approaches examined molecular level interactions of both drugs with the SLC transporters [organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT) and multi-drug and toxic compound extrusion proteins (MATE1)] and amisulpride with the ABC transporter (P-glycoprotein). The distribution of [3H]amisulpride in wildtype and 3×transgenic AD mice was examined using in situ brain perfusion experiments. Western blots determined transporter expression in mouse and human brain capillaries .ResultsIn vitro BBB and in silico transporter studies indicated that [3H]amisulpride and [3H]haloperidol were transported by the influx transporter, OCT1, and efflux transporters MATE1 and PMAT. Amisulpride did not have a strong interaction with OCTN1, OCTN2, P-gp, BCRP or MRP and could not be described as a substrate for these transporters. Amisulpride brain uptake was increased in AD mice compared to wildtype mice, but vascular space was unaffected. There were no measurable changes in the expression of MATE1, MATE2, PMAT OCT1, OCT2, OCT3, OCTN1, OCTN2 and P-gp in capillaries isolated from whole brain homogenates from the AD mice compared to wildtype mice. Although, PMAT and MATE1 expression was reduced in capillaries obtained from specific human brain regions (i.e. putamen and caudate) from AD cases (Braak stage V–VI) compared to age matched controls (Braak stage 0–II).ConclusionsTogether our research indicates that the increased sensitivity of individuals with Alzheimer’s to amisulpride is related to previously unreported changes in function and expression of SLC transporters at the BBB (in particular PMAT and MATE1). Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for individuals with AD.

General Overview of Organic Cation Transporters in Brain

“…OCT1 mRNA was also detected in the hippocampus of mice and in the choroid plexus (CP) of mice and rats (Baganz et al 2008;Choudhuri et al 2003;Duan and Wang 2013). A relatively low expression of OCT1 was observed in small blood vessels isolated from brains of humans, rats, and mice (Chaves et al 2020;Geier et al 2013;Lin et al 2010;Sekhar et al 2019;Wu et al 2015b). In cultured rat brain endothelial cells, rOct1 was located to the luminal and abluminal membranes with higher luminal expression (Lin et al 2010).…”

“…The monoamine neurotransmitter transporters exhibit transmitter/Na + /Cl À stoichiometries of 1:1:1 (NET), 1:2:1 (DAT), and 1:1:1 (SERT) (Kristensen et al 2011;Torres et al 2003). In SERT cotransport of 5-HT with Na + Net: (Lorang et al 1994;Pacholczyk et al 1991;Schroeter et al 2000;Torres et al 2003), Dat: (Cerruti et al 1993;Ciliax et al 1995;Freed et al 1995;Hersch et al 1997;Hoffman et al 1998;Holleran et al 2020;Lorang et al 1994;Nirenberg et al 1996Nirenberg et al , 1997aRevay et al 1996;Torres et al 2003), Sert: (Bengel et al 1998;Brust et al 2000;Hoffman et al 1998;Pickel and Chan 1999;Qian et al 1995;Sur et al 1996;Tao-Cheng and Zhou 1999;Zhou et al 1998) (Bengel et al 1998;Brust et al 2000;Cerruti et al 1993;Chang et al 1996;Hoffman et al 1998;Pickel and Chan 1999;Qian et al 1995;Sur et al 1996;Tao-Cheng and Zhou 1999;Torres et al 2003;Zhou et al 1998), Oct1: (Baganz et al 2008;Choudhuri et al 2003;Duan and Wang 2013;Lin et al 2010;Sekhar et al 2019;…”

Drug-Drug Interactions at Organic Cation Transporter 1

“…In contrast, prazosin could reduce the uptake of amisulpride in hCMEC/D3 cells but not in bEnd.3 cells. The accumulation of amisulpride was not affected by haloperidol in either cell line ( Sekhar et al, 2017 ). Conversely, the uptake of haloperidol could be significantly reduced by amantadine, prazosin and amisulpride in Caco-2 cells ( Kang et al, 2006 ).…”

“…Ranitidine, a known OCT1 inhibitor, could significantly reduce the cytotoxicity of pentamidine and furamidine in CHO-hOCT1 cells ( Ming et al, 2009 ). In addition, Sekhar et al reported that pentamidine was a substrate for OCT1 transporter at the BBB ( Sekhar et al, 2017 ). The OCT1 inhibitor amantadine could decrease the accumulation of pentamidine in hCMEC/D3 and bEnd.3 cell lines.…”

This was the year that was: brain barriers and brain fluid research in 2019

“…However, disease states affect the BBB and the NVU at many levels. For example, there are changes in BBB transport in stroke, AD and psychiatric disorders [153][154][155]. Krueger et al [156] recently highlighted the importance of endothelial edema after stroke.…”