title: Adenosine receptor signaling modulates permeability of the blood-brain barrier.
abstract: The blood-brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the CNS and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A(1) and A(2A) AR activation facilitated the entry of intravenously administered macromolecules, including large dextrans and antibodies to β-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A(2A) agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A(1) or A(2A) ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad-spectrum AR agonist, intravenously administered anti-β-amyloid antibody was observed to enter the CNS and bind β-amyloid plaques in a transgenic mouse model of Alzheimer's disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson's disease, multiple sclerosis and cancers of the CNS.
authors.affiliation: Department of Microbiology and Immunology, Cornell University, College of Veterinary Medicine, Ithaca, New York 14853, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Carman
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Mills
authors.forename: Antje
authors.initials: A
authors.lastname: Krenz
authors.forename: Do-Geun
authors.initials: DG
authors.lastname: Kim
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Bynoe
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010539:Permeability; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000502:physiology*; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D003911:Dextrans; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; C430916:regadenoson