PMC:6194691 / 187189-190783 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-7223890-30706590","span":{"begin":1054,"end":1056},"obj":"7223890"},{"id":"30340614-6742132-30706591","span":{"begin":1058,"end":1060},"obj":"6742132"},{"id":"30340614-590401-30706592","span":{"begin":1062,"end":1065},"obj":"590401"},{"id":"30340614-4424717-30706593","span":{"begin":1067,"end":1070},"obj":"4424717"},{"id":"30340614-4366438-30706594","span":{"begin":1439,"end":1441},"obj":"4366438"},{"id":"30340614-2396537-30706595","span":{"begin":1471,"end":1473},"obj":"2396537"},{"id":"30340614-3971148-30706596","span":{"begin":1475,"end":1478},"obj":"3971148"},{"id":"30340614-11120756-30706597","span":{"begin":1659,"end":1661},"obj":"11120756"},{"id":"30340614-16639426-30706598","span":{"begin":1746,"end":1749},"obj":"16639426"},{"id":"30340614-23434588-30706599","span":{"begin":2224,"end":2227},"obj":"23434588"},{"id":"30340614-23812703-30706600","span":{"begin":2421,"end":2424},"obj":"23812703"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Conclusion\nThis review has assessed the evidence from a number of different sources regarding the routes and mechanisms of elimination of substances from the brain parenchyma. Early studies comprehensively and admirably reviewed by Bradbury [55] and by Davson and Segal [56] revealed that there were two important routes, across the blood–brain barrier and via cerebrospinal fluid (CSF). For glucose, O2 and CO2 it was obvious that exchanges across the blood–brain barrier were dominant. At the other extreme for sucrose and inulin the concentrations in the parenchyma followed those in CSF much more closely than those in blood plasma. For Na+ and Cl− it was clear that both routes were important. For certain specific substances, e.g. Ca2+, Mg2+ and some vitamins and hormones the major route of entry is secretion by the choroid plexuses followed by distribution around the brain in CSF. However, the discovery of specific transporters for many substances at the blood–brain barrier and the finding, based largely on the work of Cserr and associates [82, 83, 126, 525], that efflux of solutes from the parenchyma to CSF was slow with half-lives of many hours led to the view that entry of most substances to the parenchyma was via the blood–brain barrier.\nThere were early suggestions that movements of large molecules between the parenchyma and CSF could be faster than seen in Cserr’s work. The first of these was the work of Wagner [68] followed by Rennels et al. [69, 135] on entry and exit of horseradish peroxidase. Within an hour of being added to CSF, it could be seen outlining blood vessels deep in the parenchyma. Somewhat later Shibata et al. [62] found that the half-life of inulin was shorter than expected and Groothuis et al. [131] found that when rats were anaesthetized with barbiturates the half-life for sucrose was as Cserr had seen with albumin, but when animals were either awake or anaesthetized with ketamine/zylazine the half-life was much shorter (see Table 1).\nThe recent explosion of interest in perivascular routes for delivery to and removal of substances from the parenchyma stems largely from observations made using two photon fluorescence microscopy and magnetic resonance imaging [25, 526]. These led to the proposal that there is a “glymphatic pathway” through which CSF flows into and within the parenchyma propelling “the waste products of metabolism into the paravenous space” [136]. As discussed in this review there is convincing evidence for perivascular routes of access to the parenchyma from CSF and also exit from the parenchyma to CSF and/or lymph. However, the balance of available evidence does not support a “glymphatic pathway” for flow through the parenchyma.\nPerivascular pathways are the principal routes of elimination of sucrose, inulin, and serum albumin. The blood–brain barrier is the principal site of efflux of many solutes including CO2, O2, glucose, lactate, K+, amino acids, many lipid soluble substances, many substrates of the SLC transporters (Sect. 4.2.2) and a few substrates carried across the endothelial cells by transcytosis. Both routes are important for movements of Na+, Cl− and water and both will be important in processes like the development and resolution of oedema (not considered in this review). With important exceptions including Na+, and Cl−, the available evidence can be summarized with a broad generalization: if there is a transport mechanism for a substance at the blood–brain barrier, then the blood–brain barrier is more important than perivascular pathways for the elimination of that substance."}

{"project":"2_test","denotations":[{"id":"30340614-7223890-30706590","span":{"begin":1054,"end":1056},"obj":"7223890"},{"id":"30340614-6742132-30706591","span":{"begin":1058,"end":1060},"obj":"6742132"},{"id":"30340614-590401-30706592","span":{"begin":1062,"end":1065},"obj":"590401"},{"id":"30340614-4424717-30706593","span":{"begin":1067,"end":1070},"obj":"4424717"},{"id":"30340614-4366438-30706594","span":{"begin":1439,"end":1441},"obj":"4366438"},{"id":"30340614-2396537-30706595","span":{"begin":1471,"end":1473},"obj":"2396537"},{"id":"30340614-3971148-30706596","span":{"begin":1475,"end":1478},"obj":"3971148"},{"id":"30340614-11120756-30706597","span":{"begin":1659,"end":1661},"obj":"11120756"},{"id":"30340614-16639426-30706598","span":{"begin":1746,"end":1749},"obj":"16639426"},{"id":"30340614-23434588-30706599","span":{"begin":2224,"end":2227},"obj":"23434588"},{"id":"30340614-23812703-30706600","span":{"begin":2421,"end":2424},"obj":"23812703"}],"text":"Conclusion\nThis review has assessed the evidence from a number of different sources regarding the routes and mechanisms of elimination of substances from the brain parenchyma. Early studies comprehensively and admirably reviewed by Bradbury [55] and by Davson and Segal [56] revealed that there were two important routes, across the blood–brain barrier and via cerebrospinal fluid (CSF). For glucose, O2 and CO2 it was obvious that exchanges across the blood–brain barrier were dominant. At the other extreme for sucrose and inulin the concentrations in the parenchyma followed those in CSF much more closely than those in blood plasma. For Na+ and Cl− it was clear that both routes were important. For certain specific substances, e.g. Ca2+, Mg2+ and some vitamins and hormones the major route of entry is secretion by the choroid plexuses followed by distribution around the brain in CSF. However, the discovery of specific transporters for many substances at the blood–brain barrier and the finding, based largely on the work of Cserr and associates [82, 83, 126, 525], that efflux of solutes from the parenchyma to CSF was slow with half-lives of many hours led to the view that entry of most substances to the parenchyma was via the blood–brain barrier.\nThere were early suggestions that movements of large molecules between the parenchyma and CSF could be faster than seen in Cserr’s work. The first of these was the work of Wagner [68] followed by Rennels et al. [69, 135] on entry and exit of horseradish peroxidase. Within an hour of being added to CSF, it could be seen outlining blood vessels deep in the parenchyma. Somewhat later Shibata et al. [62] found that the half-life of inulin was shorter than expected and Groothuis et al. [131] found that when rats were anaesthetized with barbiturates the half-life for sucrose was as Cserr had seen with albumin, but when animals were either awake or anaesthetized with ketamine/zylazine the half-life was much shorter (see Table 1).\nThe recent explosion of interest in perivascular routes for delivery to and removal of substances from the parenchyma stems largely from observations made using two photon fluorescence microscopy and magnetic resonance imaging [25, 526]. These led to the proposal that there is a “glymphatic pathway” through which CSF flows into and within the parenchyma propelling “the waste products of metabolism into the paravenous space” [136]. As discussed in this review there is convincing evidence for perivascular routes of access to the parenchyma from CSF and also exit from the parenchyma to CSF and/or lymph. However, the balance of available evidence does not support a “glymphatic pathway” for flow through the parenchyma.\nPerivascular pathways are the principal routes of elimination of sucrose, inulin, and serum albumin. The blood–brain barrier is the principal site of efflux of many solutes including CO2, O2, glucose, lactate, K+, amino acids, many lipid soluble substances, many substrates of the SLC transporters (Sect. 4.2.2) and a few substrates carried across the endothelial cells by transcytosis. Both routes are important for movements of Na+, Cl− and water and both will be important in processes like the development and resolution of oedema (not considered in this review). With important exceptions including Na+, and Cl−, the available evidence can be summarized with a broad generalization: if there is a transport mechanism for a substance at the blood–brain barrier, then the blood–brain barrier is more important than perivascular pathways for the elimination of that substance."}