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.
Highlights
Research into amisulpride use in Alzheimer’s disease (AD) implicates blood–brain barrier (BBB) dysfunction in antipsychotic sensitivity
Emerging evidence from research into amisulpride use in older people with Alzheimer’s disease (AD) psychosis suggests that blood– brain barrier (BBB) dysfunction may be an important contributor to this heightened sensitivity [3, 4]
organic cation transporters (OCT), organic cation transporters novel (OCTN), plasma membrane monoamine transporter (PMAT) and multidrug and toxic compound extrusion proteins (MATEs) involvement Involvement of OCTs in [3H]amisulpride uptake was investigated by incubating hCMEC/D3 and bEnd.3 cells with the, organic cation transporter 1 (OCT1) and 2 substrate, amantadine, the OCT1 and 3 substrate, prazosin, and the OCT3 substrate, corticosterone (Additional file 1: Figure S4). [3H]amisulpride accumulation did not change in the presence of amantadine in hCMEC/D3 cells, but significantly increased by 84% in bEnd.3 cells
Summary
Research into amisulpride use in Alzheimer’s disease (AD) implicates blood–brain barrier (BBB) dysfunction in antipsychotic sensitivity. In an open treatment study which used amisulpride use in older people with AD psychosis and very late-onset (> 60 years) schizophrenia-like psychosis (VLOSLP), treatment response and parkinsonism occurred at very low doses (25–75 mg/day AD, 50–100 mg/day VLOSLP), and at correspondingly low blood drug concentrations (40– 100 ng/ml AD, 40–169 ng/ml VLOSLP) due to higher than anticipated striatal dopamine D2/3 receptor occupancies (caudate occupancy, steady state treatment, 50 mg/day amisulpride; 41–83% AD, 41–59% VLOSLP) [3, 10,11,12] These findings strongly implicate age and AD-specific changes in central pharmacokinetics in antipsychotic drug sensitivity, at the BBB, which controls drug entry through the expression of transporters [13]. They suggest that amisulpride [14, 15] is a sufficiently sensitive tool with which to probe BBB functionality
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