PMC:6194691 / 14266-17652
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6194691","sourcedb":"PMC","sourceid":"6194691","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6194691","text":"Removal of substances from the brain parenchyma: overview\nThere are three possible pathways by which substances can be removed from the brain parenchyma: via transport to blood across the blood–brain barrier; via exit to CSF or possibly directly to lymph followed by subsequent transfer to blood; or via metabolism to different substances. The relative importance of each of these pathways as a mechanism of removal depends on the nature of the substance under consideration.\nIn the case of metabolism, though the original substance is removed, the resulting metabolites still eventually require elimination as well. Glucose for instance is largely removed by metabolism to CO2 and water but these species must then exit the brain. At the opposite extreme inorganic ions such as Na+ and K+ cannot be metabolized and are removed by efflux in their original forms.\nConvection of fluid along perivascular spaces facilitates efflux (as well as influx) of a range of large polar substances such as serum albumin, inulin, sucrose, and various dextrans and polyethylene glycols. Efflux of these substances from parenchyma to CSF (or lymph) via the perivascular spaces is relatively slow, taking hours, but it is still much more rapid than could be supported by diffusion over the large distances involved suggesting that it is occurring by some sort of flow (see Sect. 3.2). The exact ways in which perivascular influx and efflux of solutes and water take place have been controversial as considered in some detail in Sect. 3. Tarasoff-Conway et al. [52] have addressed the issue of perivascular clearance with particular regard to one particular solute, amyloid-β. Brinker et al. [53], Hladky and Barrand [41], Simon and Iliff [39], Coles et al. [1], Abbott et al. [40], and Benveniste et al. [54] have summarized the evidence concerning perivascular transport from various perspectives.\nTransport across the blood–brain barrier is the dominant mechanism for removal of water and CO2 from brain parenchyma (for discussion and references see [4]). Molecules less lipid soluble or somewhat larger than H2O need specific transporters in the endothelial cell membranes of the barrier, e.g. for glucose GLUT1, which is found in both luminal and abluminal membranes. Transporters are present for a large number of substances [20, 31, 46, 55–58] (see Sect. 4.2). Certain larger solutes, e.g. insulin [59], transferrin [60, 61] and β-amyloid [62], may be transported across the blood–brain barrier by transcytosis [36, 63, 64] (see Sect. 4.3).\nMany of the transporters found at the blood–brain barrier are capable of mediating not only efflux but also influx and have been studied more thoroughly from this standpoint. Other transporters, e.g. the ABC efflux pumps that are present in the luminal membranes of the endothelial cells (see Sect. 4.2.1), transfer many exogenous substances in an outward direction from endothelial cells to blood fuelled by the energy derived from ATP hydrolysis. This outward movement serves to decrease blood-to-brain influx as substances that enter the endothelial cells (or even just the luminal membranes of the cells) are returned to blood before they enter the brain proper. ABC transporters may also promote brain-to-blood efflux if there is some means for the substances to enter the endothelial cells across the abluminal membranes (see Sects. 4.2.1 and 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