Interaction between nicotine and MPTP/MPP+ in rat brain endothelial cells.
To examine the interaction between nicotine and MPTP/MPP+ in the blood-brain barrier, cellular uptake of MPTP and MPP+ was studied in the presence of nicotine and several compounds, including MPTP/MPP+ analogs and a specific inhibitor of organic cation transporter (OCT) in an adult rat brain microvascular endothelial cell line (ARBEC). The kinetic properties of the uptake of MPTP, MPP+, and nicotine were also examined. In addition, a microdialysis study was performed to evaluate the in vivo effect of nicotine (i.p.) on extracellular levels of MPTP and MPP+ in the brain after intravenous administration of MPTP. The results showed that uptake of MPTP, MPP+, and nicotine was partly mediated by a carrier system that was sensitive to decynium22, a specific OCT inhibitor. RT-PCR showed the presence of OCT1 mRNA in ARBEC. Capacity for uptake of MPTP and nicotine was much higher than that for MPP+ (Km and Vm values of 10.94+/-1.44 microM and 0.049+/-0.007 pmol/mg s, respectively, for MPP+, compared to values of 35.75+/-0.85 microM and 40.95+/-3.56 pmol/mg s for MPTP and 25.29+/-6.44 microM and 51.15+/-14.18 pmol/mg s for nicotine). In addition, nicotine competitively inhibited the uptake of both MPTP and MPP+, with inhibition constants (Ki) of 328 microM and 210 microM, respectively. In vivo microdialysis results showed that nicotine significantly reduced brain extracellular levels of MPTP in the first 30 min (507.4+/-8.5 ng/ml vs. 637.9+/-30.8 ng/ml with and without nicotine pre-treatment, respectively), but did not have significant effect on those of MPP+. In conclusion, nicotine can inhibit in vitro cellular uptake and in vivo transfer of MPTP across the blood-brain barrier, which can be mediated by multiple pathways including OCT1.
Liou
Horng-Huei
HH
Department of Pharmacology, College of Medicine, National Taiwan University, and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Hsu
Hao-Jui
HJ
Tsai
Yuan-Feen
YF
Shih
Chin-Yu
CY
Chang
Yu-Chia
YC
Lin
Chun-Jung
CJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D003367:Cotinine / Q000378:metabolism; D003627:Data Interpretation, Statistical; D015259:Dopamine Agents / Q000378:metabolism / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017711:Nonlinear Dynamics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D018722:Nicotinic Agonists; D009538:Nicotine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003367:Cotinine