Role of two efflux proteins, ABCB1 and ABCG2 in blood-brain barrier transport of bromocriptine in a murine model of MPTP-induced dopaminergic degeneration.
OBJECTIVE
MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported.


METHODS
We have investigated the transport of bromocriptine through the blood-brain barrier (BBB) in a MPTP model to understand the influence of the dopaminergic degeneration on ABCB1 and ABCG2.


RESULTS
We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p less than 0.001) suggesting either disruption of BBB or alteration of active efflux of the drug. In situ brain perfusion of [14C]- sucrose and [3H]-inulin did not evidenced a BBB disruption. Studies of ABCB1 and ABCG2 activity showed that MPTP intoxication did not alter their functionality. Conversely, ABCG2 expression studied on brain capillaries from MPTP-treated mice was decreased (1.3-fold, p less than 0.05) and ABCB1 expression increased (1.43-fold, p less than 0.05) as an off-setting of brain transport.


CONCLUSIONS
These data demonstrate that MPTP intoxication does not alter the BBB permeability. However, bromocriptine brain distribution is increased in MPTP animals. Hence, MPTP may interact with another transport mechanism such as uptake and/or other efflux transporters. Inflammation and Parkinson's-like lesions induced by MPTP intoxication could lead to modification of drug pharmacokinetics and have clinical consequences, such as neurotoxicity.
Vautier
Sarah
S
Department of Clinical Pharmacy EA 2706, University Paris Sud XI, Chatenay-Malabry, France. sarahvautier@hotmail.com
Milane
Aline
A
Fernandez
Christine
C
Chacun
Helene
H
Lacomblez
Lucette
L
Farinotti
Robert
R
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001971:Bromocriptine / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D020267:MPTP Poisoning / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000978:Antiparkinson Agents; D001971:Bromocriptine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C507084:Abcb1b protein, mouse