학술논문
Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer's disease.
Document Type
Academic Journal
Author
Sekhar GN; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Fleckney AL; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Boyanova ST; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Rupawala H; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Lo R; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Wang H; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Farag DB; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Faculty of Pharmacy, Misr International University, Cairo, 11431, Egypt.; Rahman KM; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK.; Broadstock M; Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK.; Maurice Wohl Clinical Neuroscience Institute, King's College London, 125 Coldharbour Lane, Camberwell, London, SE5 9N, UK.; Reeves S; Division of Psychiatry, Faculty of Brain Sciences, University College London, 149 Tottenham Court Road, London, W1T 7NF, UK.; Thomas SA; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, Waterloo, London, SE1 9NH, UK. sarah.thomas@kcl.ac.uk.
Source
Publisher: Biomed Central Country of Publication: England NLM ID: 101553157 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-8118 (Electronic) Linking ISSN: 20458118 NLM ISO Abbreviation: Fluids Barriers CNS Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Research 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.
Methods: The accumulation of [3 H]amisulpride (3.7-7.7 nM) and [ 3 H]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 [ 3 H]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 .
Results: In vitro BBB and in silico transporter studies indicated that [3 H]amisulpride and [ 3 H]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).
Conclusions: Together 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.
Methods: The accumulation of [
Results: In vitro BBB and in silico transporter studies indicated that [
Conclusions: Together 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.