Metabolite transport across central nervous system barriers

Abstract

Metabolomic analysis of cerebrospinal fluid (CSF) is used to improve diagnostics and pathophysiological understanding of neurological diseases. Alterations in CSF metabolite levels can partly be attributed to changes in brain metabolism, but relevant transport processes influencing CSF metabolite concentrations should be considered. The entry of molecules including metabolites into the central nervous system (CNS), is tightly controlled by the blood-brain, blood-CSF, and blood-spinal cord barriers, where aquaporins and membrane-bound carrier proteins regulate influx and efflux via passive and active transport processes. This report therefore provides reference for future CSF metabolomic work, by providing a detailed summary of the current knowledge on the location and function of the involved transporters and routing of metabolites from blood to CSF and from CSF to blood.

Keywords: Blood-brain barrier; blood-CSF barrier; brain metabolism; metabolomics; transport mechanisms.

Figure 1.

Transporters at the blood-CSF barrier and blood-brain barrier. Simplified illustration of the blood-brain barrier without the adjacent basement membrane, pericytes and astrocyte end feet located at the abluminal endothelial side. Only transporters of which the exact cellular location is known are depicted in the figure. Red circles indicate transporters of which location was demonstrated in human cells; grey circles indicate the transporter location was shown in animal cells. Arrows indicate the presumed main transport direction. In case of solute carriers capable of bidirectional transport, the physiological most relevant direction is indicated. Of note, the following transporters are present at the barriers but not included in the figure because their cellular location has not yet been shown: OCTN1, OCTN2, ASCT1, ASCT2, 4F2HC, ENT1, CTL1, CTL2, MATE1, MATE2, RFC, BGT1, ABCA2, ABCA8, SUR1 for the blood-brain barrier and ABCA8, SGLT2, CAT1, LAT1, EAAT1, 4F2HC, ENT1, CRT1, MATE1, PCFT, BGT1, MCT1 MCT4 for the blood-CSF barrier. Image created in BioRender.com.