Transport of the Nucleoside, Thymidine, in the Central Nervous System: The Blood-Cerebrospinal Fluid and Blood-Brain Barriers

Abstract

The exchanges between blood, on the one hand, and the cerebrospinal fluid (CSF) and brain-tissue on the other, are governed by so-called “barriers”, which may be assessed quantitatively by measuring rate of uptake of a given solute from blood into the CSF — the blood-CSF barrier — and into the brain tissue — the blood-brain barrier. From these uptakes a simple unidirectional transfer coefficient, Kin, can usually be derived. The two barriers are not independent since the uptake into one component of the central nervous system may include a contribution from, or to, the other because of the free diffusional communication between brain-tissue and CSF across the ependymal and pia-glial membranes. Typically, this interchange is seen with relatively lipid-soluble substances, such as the thioureas or ethyl alcohol; simultaneous measurement of uptake into brain and CSF indicates that the brain comes much more rapidly into equilibrium with blood than does the CSF. This is due, essentially, to the different geometries of the systems. As Figure 1 illustrates, direct penetration from blood into CSF takes place almost exclusively within the ventricles across the choroidal epithelium; once outside the ventricles, the fluid is no longer exposed directly to the blood, so that further gains from this can only be achieved by diffusion from the brain tissue. The volume of the subarachnoid fluid is several times greater than that of the ventricular fluid, and this geometrical arrangement means that the final equilibration with blood is delayed by the requirement that CSF should flow from ventricles to subarachnoid spaces. If there were no additions to the CSF after if had left the ventricles, the maximum value of Kin would be given by the turnover-constant of the CSF; on average this represents a renewal-rate of some 0.045% per minute to give a constant of 4.5×10−3min−1. In practice we find, with lipid-soluble solutes such as the thioureas or ethyl alcohol, much larger values of Kin (Figure 2); thus with ethyl alcohol the rate of equilibration in rabbit has a half-life of one or two minutes, giving a Kin of 7 to 3.5×10−1min−1.