Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 100, Issue 9, Pages 3924-3938Publisher
WILEY-BLACKWELL
DOI: 10.1002/jps.22594
Keywords
blood-brain barrier; blood-cerebrospinal fluid barrier; in vitro models; transporters; CNS; plasma membrane monoamine transporter; 1-methyl-4-phenylpyridinium; TR-BBB13 cells; TR-CSFB3 cells
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [21590075] Funding Source: KAKEN
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This study investigated the expression and functional roles of rat plasma membrane monoamine transporter (rPMAT) in the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier by using in vitro brain barrier model cells (TR-BBB13 and TR-CSFB3 cells) and multiple in vivo experimental techniques. Quantitative reverse transcription-polymerase chain reaction analysis showed relatively high expression of rPMAT mRNA in TR-BBB13 and TR-CSFB3 cells. 1-Methyl-4-phenylpyridinium (MPP(+)) was transported into rPMAT-expressing cells in a sodium-independent manner. [(3)H]MPP(+) was taken up concentration dependently by TR-BBB13 and TR-CSFB3 cells with K(m) values similar to that of rPMAT-expressing cells. [(3)H]MPP(+) transports into these cells were markedly inhibited by serotonin, dopamine, and cationic drugs. rPMAT small interfering RNA (siRNA) significantly suppressed the [(3)H]MPP(+) uptake by TR-BBB13 cells. Intracerebrally injected [(3)H]MPP(+) was eliminated from the brain parenchymal region, whereas brain [(3)H]MPP(+) uptake did not increase with time during in situ brain perfusion, suggesting that the brain-to-blood transport across the BBB predominates over the blood-to-brain transport. Brain microdialysis studies revealed that the elimination across the BBB was significantly decreased by coperfusion of unlabelled MPP(+), serotonin, or dopamine. [(3)H]MPP(+) was also eliminated from the CSF. These findings suggest that PMAT in brain barriers functions as the brain-to-blood transporter to regulate brain concentrations of organic cations including monoamines and cationic neurotoxins. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3924-3938, 2011
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