Drug resistance in epilepsy: the role of the blood-brain barrier.
The blood-brain barrier (BBB) is formed by the endothelial cells lining the brain microvessels. Complex tight junctions linking adjacent endothelial cells make brain capillaries around 100 times tighter than peripheral capillaries to small hydrophilic molecules. As a result, drugs required to act in the brain, including anti-epileptic drugs (AEDs), have generally been made lipophilic, and are thus able to cross the brain endothelium via the lipid membranes. However, such lipophilic drugs are potential substrates for efflux carriers of the BBB, particularly P glycoprotein (Pgp), predominantly located on the endothelial luminal membrane. It is estimated that up to 50% of drug candidates may be substrates for Pgp. The barrier phenotype of the brain endothelium is induced and maintained by chemical factors released by brain cells, particularly perivascular astrocytic end feet. In several neuropathological conditions, the BBB is disturbed, either as a result of pathology of the endothelium, or of the cells responsible for barrier induction and maintenance. During epileptic attacks, there may be transient BBB opening in the epileptogenic focus. There is evidence that under such pathological conditions, 'second line defence' mechanisms in perivascular glia may be up-regulated, including expression of Pgp and other drug efflux transporters. This complicates interpretation of drug resistance in epilepsy, and therapeutic strategies.
Abbott
N Joan
NJ
Blood Brain Barrier Research Group, Centre for Neuroscience Research, King's College London, UK.
Khan
Ehsan U
EU
Rollinson
Christopher M S
CM
Reichel
Andreas
A
Janigro
Damir
D
Dombrowski
Stephen M
SM
Dobbie
Michael S
MS
Begley
David J
DJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001253:Astrocytes / Q000378:metabolism; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000502:physiology*; D002831:Choroid Plexus / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation; D019450:Genes, MDR; D000882:Haplorhini; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D008563:Membrane Lipids