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

Brain Pathol. 2012 Mar;22(2):175-87. doi: 10.1111/j.1750-3639.2011.00517.x. Epub 2011 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Benzoates / pharmacology
  • Benzylamines / pharmacology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / physiopathology
  • Brain / blood supply
  • Brain / pathology
  • Brain / physiopathology
  • Brain Edema / drug therapy*
  • Brain Edema / etiology
  • Brain Edema / physiopathology
  • Brain Ischemia / complications
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / physiopathology
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Hydrocarbons, Fluorinated / pharmacology
  • Liver X Receptors
  • Mice
  • Mice, Inbred C57BL
  • Middle Cerebral Artery / drug effects
  • Middle Cerebral Artery / metabolism
  • Middle Cerebral Artery / physiopathology
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Orphan Nuclear Receptors / metabolism*
  • Sulfonamides / pharmacology
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Benzoates
  • Benzylamines
  • GW 3965
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Multidrug Resistance-Associated Proteins
  • Orphan Nuclear Receptors
  • Sulfonamides
  • TO-901317
  • Abcb1b protein, mouse
  • multidrug resistance-associated protein 1