title: Adenosine receptor agonist NECA increases cerebral extravasation of fluorescein and low molecular weight dextran independent of blood-brain barrier modulation.
abstract: Conventional methods for therapeutic blood-brain barrier (BBB) disruption facilitate drug delivery but are cumbersome to perform. A previous study demonstrated that adenosine receptor (AR) stimulation by 5'-N-ethylcarboxamide adenosine (NECA) increased the extravasation of intravascular tracers into the brain and proposed that AR agonism may be an effective method for therapeutic BBB disruption. We attempted to confirm the extravasation of tracers into the brain and also investigated tracer extravasation into peripheral organs and tracer retention in the blood. We found that NECA not only increased the extravasation of intravascular fluorescein and low molecular weight dextran into the brain of mice but also increased the concentrations of these tracers in the blood. In fact, the brain:blood ratio-normalized BBB permeability for either tracer is actually decreased by NECA administration. Elevated blood urea nitrogen levels in mice following NECA treatment suggested that renal function impairment was a probable cause of tracer retention. Therefore, NECA has almost no effect on the extravasation of intravascular Evans blue dye (EBD), an albumin-binding tracer with little renal clearance. Rather than inducing BBB disruption, our study demonstrated that NECA increased tracer extravasation into the brain by increasing the concentration gradient of the tracer across the BBB.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Ya Lan
authors.initials: YL
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
authors.forename: Kate Hsiurong
authors.initials: KH
authors.lastname: Liao
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Translational Medicine Research Center, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Ted Weita
authors.initials: TW
authors.lastname: Lai
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose; D001806:Blood Urea Nitrogen; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D003911:Dextrans / Q000493:pharmacokinetics*; D019793:Fluorescein / Q000493:pharmacokinetics*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics*; D008297:Male; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology*; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced
chemical_list: D001786:Blood Glucose; D003911:Dextrans; D005456:Fluorescent Dyes; D058906:Purinergic P1 Receptor Agonists; D019830:Adenosine-5'-(N-ethylcarboxamide); D019793:Fluorescein