Abstract
Organic cation transporters (OCTs) participate in the handling of compounds in kidneys and at the synaptic cleft. Their role at the blood-brain barrier (BBB) in brain drug delivery is still unclear. The presence of OCT1,2,3 (SLC22A1-3) in mouse, rat and human isolated brain microvessels was investigated by either qRT-PCR, quantitative proteomics and/or functional studies. BBB transport of the prototypical substrate [3H]-1-methyl-4-phenylpyridinium ([3H]-MPP+) was measured by in situ brain perfusion in six mouse strains and in Sprague Dawley rats, in primary human brain microvascular endothelial cells seeded on inserts, in the presence or absence of OCTs and a MATE1 (SLC49A1) inhibitor. The results show negligible OCT1 (SLC22A1) and OCT2 (SLC22A2) expression in either mice, rat or human brain microvessels, while OCT3 expression was identified in rat microvessels by qRT-PCR. The in vitro human cellular uptake of [3H]-MPP+ was not modified by OCTs/MATE-inhibitor. Brain transport of [3H]-MPP+ remains unchanged between 2- and 6-month old mice, and no alteration was observed in mice and rats with inhibitors. In conclusion, the evidenced lack of expression and/or functional OCTs and MATE at the BBB allows the maintenance of the brain homeostasis and function as it prevents an easy access of their neurotoxicant substrates to the brain parenchyma.
Highlights
Neurons and glial cells forming the brain parenchyma are surrounded by the interstitial fluid (ISF)
The mRNA levels of five transporters (Oct1-3, Mate1, Mdr1a) were analyzed and compared in the Swiss, FVB and C57BL/6 mice strains by Quantitative Real-Time PCR (qRT-PCR) (n = 3, 5 mice per n)
The Oct1 mRNA contents were below the limit of detection (CT = undetermined), suggesting that this solute carrier (SLC) transporter is not expressed at the blood-brain barrier (BBB) regardless of the mice strain
Summary
Neurons and glial cells forming the brain parenchyma are surrounded by the interstitial fluid (ISF). Endothelial or epithelial cells held together by tight junctions are found constituting barriers to the paracellular route and controlling the transcellular molecular exchanges between the blood and the brain fluid spaces. The blood-brain barrier (BBB), formed by the cerebrovascular endothelial cells, plays a critical role in regulating the molecular trafficking between the blood and the ISF. Compounds may cross the BBB and reach the brain parenchyma/ISF through a transcellular route, namely passive and/or carrier-mediated transport. The concentration of compounds within the ISF, and its composition, is affected by neurons and glial cells due to the expression of neurotransmitter “uptake” transporters known as DAT, NET, SERT (SLC6A family) and OCT2-3 (SLC22A2-3), potassium channels (Kir 4.1) and glutamate transporters (SLC1A)
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