The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) with the human blood–brain barrier in vitro

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Abstract

The blood–brain barrier (BBB) is a biological firewall that carefully regulates the cerebral microenvironment by acting as a physical, metabolic and transport barrier. This selectively permeable interface was modelled using the immortalised human cerebral microvascular endothelial cell line (hCMEC/D3) to investigate interactions with the cationic amino acid (CAA) L-arginine, the precursor for nitric oxide (NO), and with asymmetric dimethylarginine (ADMA), an endogenously derived analogue of L-arginine that potently inhibits NO production. The transport mechanisms utilised by L-arginine are known but they are not fully understood for ADMA, particularly at the BBB. This is of clinical significance giving the emerging role of ADMA in many brain and cerebrovascular diseases and its potential as a therapeutic target. We discovered that high concentrations of ADMA could induce endothelial dysfunction in the hCMEC/D3s BBB permeability model, leading to an increase in paracellular permeability to the paracellular marker FITC-dextran (40 kDa). We also investigated interactions of ADMA with a variety of transport mechanisms, comparing the data with L-arginine interactions. The CAA transport system y+ was strongly implicated as the transport system utilised by both molecules through the use of established inhibitors. Furthermore, the expression of CAT-1, the best known protein from this group, was confirmed in the hCMEC/D3s. These data are not only important with regards to the brain, but apply to other microvascular endothelia where ADMA is a major area of investigation.
Original languageEnglish
Pages (from-to)232–242
JournalBrain research
Volume1648
Issue numberPart A
Early online date16 Jul 2016
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • Blood-Brain Barrier

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