Abstract
The Evans blue dye (EBD; 961 Da) and the sodium fluorescein dye (NaF; 376 Da) are commonly used inert tracers in blood-brain barrier (BBB) research. They are both highly charged low molecular weight (LMW) tracers with similar lipophobic profiles. Nevertheless, the EBD binds to serum albumin (69,000 Da) to become a high molecular weight (HMW) protein tracer when injected into the circulation, whereas the NaF remains an unbound small molecule in the circulation. In this study, rats were injected with equal doses of either EBD or NaF to monitor their blood and tissue distribution. The EBD was largely confined to the circulation with little accumulation in the peripheral organ and even less accumulation in the central tissue, whereas the NaF distributed more evenly between the blood and the peripheral organ but was also largely excluded from the central tissue. Importantly, the EBD crossed the BBB most effectively at the prefrontal cortex and the cerebellum, and most poorly at the striatum. In marked contrast, the NaF was evenly distributed throughout the brain. Finally, the EBD exhibited this same peculiar tissue distribution profile when administered by either bolus injection or slow infusion. Our study suggests that different regions of the brain are equally permeable to LMW inert dyes like the NaF, but are markedly different in permeability to HMW proteins such as EBD-labelled serum albumin.
Highlights
The blood-brain barrier (BBB) restricts and thereby controls the exchanges of proteins and inert chemicals between the brain and the cerebral circulation [1,2,3,4], and treatments that open the BBB are developed to facilitate brain delivery of high molecular weight (HMW) biologics and low molecular weight (LMW) drug chemicals [5,6,7,8,9]
The BBB safeguards the brain against unwanted exchanges of HMW proteins and LMW inert substances, and research in BBB has important physiological, pathological, and pharmacological implications
We report here that the HMW-way and the LMW-way across the BBB represent two distinct routes into the brain, and such distinction can be made by comparing the regions of the brain most accessible to the respective substance
Summary
The blood-brain barrier (BBB) restricts and thereby controls the exchanges of proteins and inert chemicals (those not permeable across endothelial cell membranes) between the brain and the cerebral circulation [1,2,3,4], and treatments that open the BBB are developed to facilitate brain delivery of high molecular weight (HMW) biologics (protein-based drugs) and low molecular weight (LMW) drug chemicals (small molecules) [5,6,7,8,9]. The EBD binds strongly to serum albumin (69,000 Da) to become a HMW protein tracer once in the circulation, whereas the NaF remains largely in the free, unbound and LMW form [10,11,12,13]. These properties make these two dyes ideal for studying BBB accessibility by HMW proteins and LMW chemicals, respectively. Very slowly infused EBD would more closely resemble HMW proteins that take the HMW-way into the brain
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