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.
Highlights
The blood-brain barrier (BBB) protects the brain against unwanted exchanges of chemicals and proteins and impedes therapeutic agents from entering the brain
adenosine receptor (AR) agonists decreased trans-endothelial electrical resistance (TEER), which measures paracellular resistance, across an endothelial monolayer[20,24,25], it had no effect on TEER or tracer permeability when the endothelial monolayer was co-cultured with astrocytes[22], which mimics the BBB inducing microenvironment of the brain[26,27]
The dose and route of administration for N-ethylcarboxamide adenosine (NECA) and the time point for assessment of BBB permeability were based on the original study that demonstrated the BBB disrupting effect of AR stimulation[20]
Summary
The blood-brain barrier (BBB) protects the brain against unwanted exchanges of chemicals and proteins and impedes therapeutic agents from entering the brain. Adenosine receptors (ARs) have recently been regarded as promising pharmacological targets for inducing BBB disruption[19] This notion is based on a study showing that the intravenous administration of 5′ -N-ethylcarboxamide adenosine (NECA), a broad spectrum AR agonist, increases brain extravasation of intravascular low molecular weight (LMW) and high molecular weight (HMW) dextrans[20]. Consistent with AR signaling, the efficacy by which NECA induces brain extravasation of intravascular tracers was attenuated in mice lacking either A1 or A2A receptor subtypes and in mice receiving antagonists against the ARs20 These findings could be of tremendous translational value because AR agonists are already clinically approved for other indications, and the intravenous administration of NECA is far less invasive than existing methods for disrupting the BBB. Rather than acting on the BBB directly, NECA indirectly increased the extravasation of these tracers across the BBB by increasing their concentration gradients
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