P-glycoprotein expression and function are increased in an animal model of amyotrophic lateral sclerosis.
The efflux pumps located at the blood-brain barrier (BBB) prevent drugs entering the brain. As such, efflux pumps are a major obstacle to drug brain distribution. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with little therapeutics available: riluzole is the only drug approved in its treatment. The lack of response to treatment in ALS may be, at least in part, due to increased activities of efflux pumps in relation to disease, leading to subtherapeutic brain concentrations of drugs. In the present study, we used a transgenic mouse model of ALS (G86R mSOD1 mice) to test this hypothesis. Expression and functionality of P-glycoprotein (ABCB1, P-gp) and Breast Cancer Resistance Protein (ABCG2, BCRP), two major efflux pumps, were studied. We observed an increased P-gp expression (1.5-fold) in presymptomatic mSOD1 mice compared to wild-type controls. Consistent with this, P-gp function was also increased by 1.5-fold and riluzole brain disposition was decreased by 1.7-fold in mSOD1 mice. Contrasting with this, BCRP expression and function were unaltered by the pathology. These results demonstrate that BBB transport proteins are modified in G86R mSOD1 mice ALS model. Such findings underline potential problems in extrapolating the results of animal studies to humans and developing clinical trials, especially for drugs transported by P-gp.
Paris-Sud-XI University, EA 2706, Faculty of Pharmacy, Chatenay-Malabry, France.
Aline
A
Milane
Christine
C
Fernandez
Luc
L
Dupuis
Marion
M
Buyse
Jean-Philippe
JP
Loeffler
Robert
R
Farinotti
Vincent
V
Meininger
Gilbert
G
Bensimon
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018696:Neuroprotective Agents / Q000378:metabolism; D019782:Riluzole / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
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; D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; D019782:Riluzole; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1