t0901317 and Brain-Edema

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.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoates; Benzylamines; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Endothelial Cells; Hydrocarbons, Fluorinated; Liver X Receptors; Mice; Mice, Inbred C57BL; Middle Cerebral Artery; Multidrug Resistance-Associated Proteins; Orphan Nuclear Receptors; Sulfonamides; Tight Junctions; Up-Regulation