Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease
| Autor: | Khondaker M. Rahman, Doaa B. Farag, Rachel Lo, Martin Broadstock, Huzefa Rupawala, Sarah A. Thomas, Sevda Tomova Boyanova, Alice L. Fleckney, Suzanne Reeves, Gayathri N. Sekhar, Hao Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment ATP-binding cassette transporter Pharmacology OCT1 lcsh:RC346-429 Mice Plasma membrane monoamine transporter 0302 clinical medicine Haloperidol Blood-brain barrier Aged 80 and over 0303 health sciences Organic cation transport proteins biology Chemistry MATE1 General Medicine Human brain Alzheimer's medicine.anatomical_structure Neurology Blood-Brain Barrier Female Amisulpride Antipsychotic Agents medicine.drug Mice Transgenic Blood–brain barrier Models Biological PMAT Cell Line Cellular and Molecular Neuroscience 03 medical and health sciences Developmental Neuroscience Alzheimer Disease medicine Animals Humans Antipsychotic lcsh:Neurology. Diseases of the nervous system 030304 developmental biology Binding Sites business.industry Research Endothelial Cells Membrane Transport Proteins Transporter In vitro Solute carrier family 030104 developmental biology biology.protein business Alzheimer’s 030217 neurology & neurosurgery |
| Zdroj: | Fluids and Barriers of the CNS, Vol 16, Iss 1, Pp 1-19 (2019) Sekhar, G N, Fleckney, A L, Boyanova, S T, Rupawala, H J, Lo, R, Wang, H, Farag, D, Rahman, K M, Broadstock, M, Reeves, S & Thomas, S A 2019, ' Region-specific blood–brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease ', Fluids and Barriers of the CNS, vol. 16, no. 1, 38 . https://doi.org/10.1186/s12987-019-0158-1 Fluids and Barriers of the CNS |
| DOI: | 10.1101/582387 |
| Popis: | 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 [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 . Results In 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). 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. |
| Databáze: | OpenAIRE |
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