Ontogeny of blood-brain barrier permeability to, and cerebrospinal fluid sink action on, [14C]urea

Abstract

To ascertain the ontogeny of CSF sink action on a small hydrophilic solute, we investigated the rate and extent of uptake of [14C]urea by lateral ventricle choroid plexus (CP), cisternal cerebrospinal fluid (CSF), cerebral cortex, and cerebellum in 0.5- to 4-wk-old etherized nephrectomized rats. Five hours after ip injection, radiourea penetrated the entire H2O of tissue and CSF in 1-wk-old brain; moreover, for animals 1-4 wk old there was a marked inverse relationship between age and magnitude of steady-state [14C]urea space in all regions. However, there was lack of progression (with advancing age) in distribution times to steady state, undoubtedly a reflection of the complexity of maturational factors (CSF secretion, barrier permeability, biphasic changes in cerebral blood flow, etc.) that affect solute penetration into central nervous system. Analysis of [14C]urea uptake curves for various regions at different stages of development (1 vs. 2 wk) revealed half times (slow component) that were significantly greater at 1 wk (1.2-1.4 h) than at 2 wk (0.5-0.8 h). Steady-state concentration gradients for tracer urea, plasma to CP to CSF, indicated negligible molecular sieving of urea by CP 1 wk after birth; however, after the 2nd postnatal wk CSF sink action on urea became manifest due to development of CSF secretion and molecular sieving at the blood-CSF and blood-brain barriers.

GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo

“…Analysis of lithium concentration in the PVWM by atomic absorption demonstrated that injected agents are diluted 20-to 30-fold following intraventricular injection. This is due to the direct dilution of the injectate in the volume of the CSF and the rapid turnover of CSF and drainage into the subarachnoid spaces, and our findings are entirely consistent with measurements of a range of small and large molecular weight agents (Nagaraja et al, 2005;Parandoosh and Johanson, 1982). We tested diverse GSK3b inhibitors and they all had equivalent effects, increasing OPs and OLs and promoting myelination in the PVWM.…”

Choroid Plexus–Cerebrospinal Fluid Circulatory Dynamics: Impact on Brain Growth, Metabolism, and Repair

“…Two examples are the translocation of water and amyloid peptides by aquaporins (3) and the LRP-1 transporter (3,40), respectively. Conceptualizing both plasma and CSF as potential sinks (40,44) on water and solutes will enhance pharmacotherapy to ameliorate hydrocephalus and Alzheimer's disease (3,41).…”

“…A worthy goal is to identify agents that stabilize the BCSFB and allow CP to maintain CSF formation in senescence. This would maintain CSF sink action (44) and the clearance of harmful toxins (3,41,43). Otherwise, stagnated CSF dynamics in advanced aging predisposes to the dementia of chronic hydrocephalus (41).…”

Enhanced Prospects for Drug Delivery and Brain Targeting by the Choroid Plexus–CSF Route

“…Consequently, there is paracellular diffusion of small hydrophilic solutes through CP tight junctions and onward into CSF. For example, intravascularly administered mannitol (M W = 182) and inulin polysaccharide (M W õ 5,500) penetrate into CSF (16,17) by diffusing between choroid epithelial cells rather than through them (18,19).…”