title: Liver X receptor activation enhances blood-brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells.
abstract: The blood-brain barrier (BBB) consists of dense contacts between endothelial cells, the tight junctions, which are complemented by membrane-bound transporters belonging to the ATP-binding cassette (ABC) transporter family. Liver X receptors (LXR) have previously been shown to stabilize the integrity of atherosclerotic noncerebral arteries. Their effects on ischemic cerebral vessels are still unknown. By delivering LXR agonists, T0901317 and GW3965, to mice submitted to 30 minutes intraluminal middle cerebral artery occlusion, we show that LXR activation reduces brain swelling and decreases BBB permeability by upregulating LXR's target calpastatin that deactivates calpain-1/2, stabilizing p120 catenin. p120 catenin specifically interacts with RhoA and Cdc42, inactivating the former and overactivating the latter, thus restoring the postischemic expression, phosphorylation and interaction of the tight junction proteins occludin and zona occludens-1. Moreover, LXR activation deactivates matrix metalloproteases-2/9 and inhibits microvascular apoptosis by deactivating JNK1/2 and caspase-3. In addition to the cholesterol transporters ABCA1 and ABCG1, which have previously been shown to be upregulated by LXR in noncerebral vessels, LXR activation increases the abundance of the drug transporters ABCB1 and ABCC1 on ischemic brain capillaries, as we further show. That LXR activation promotes endothelial integrity in different ways makes this receptor attractive as target for stroke therapies.
authors.affiliation: Department of Neurology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany.
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001565:Benzoates; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C507084:Abcb1b protein, mouse; C421109:multidrug resistance-associated protein 1