PMC:6194691 / 98663-102569
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":"Lactate\nWhen at rest and even more during nervous activity, there is net production of lactate within the brain parenchyma and thus there must be means for its efflux. Clearance of lactate from the brain has recently been reviewed in some detail [146] (see also footnote 26 in [4]). In brief lactic acid is transported across the blood–brain barrier by passive transport mediated by MCT1 (SLC16A1) present in both luminal and abluminal membranes. Lactate both enters and leaves the brain by this route. Lactate is generated within the brain by partial metabolism of glucose and by metabolism of glutamate [347, 348]). Under resting conditions when lactate concentrations are low, the clearance, CL = PS ~ 60–100 µL g−1 min−1 [349–352], far exceeds the expected clearance, ~ 1 µL g−1 min−1, by a strictly perivascular route.\nIt is often said that transport of lactate across the blood–brain barrier is slow (see e.g. Pardridge’s account [189]). But these statements refer to the amounts transported not the permeability. The lactate clearance (= PS product) calculated for low concentrations from the kinetic constants that Pardridge presents, Kt = 1.8 mM and Tmax = 91 nmol g−1 min−1, is 50 µL g−1 min−1, close to that stated above. Quistorff et al. [353] and Boumezbeur et al. [352] have emphasized that lactate from the periphery can be an important source of energy in the brain during heavy exercise.\nThere is clear evidence that during periods of increased neural activity the blood–brain barrier is not the only route of lactate removal from the sites of activity [354–357]. This may be particularly important in circumstances where the lactate concentration is also increased in the rest of the body, e.g. as a result of physical exercise. Under these circumstances the net transport across the blood–brain barrier is likely to be inwards [352, 353]. Other routes for efflux cannot be just perivascular transport as seen with inulin because that isn’t fast enough. One suggested explanation is perivascular transport augmented by transfer between astrocyte endfeet via gap junctions. This can lead to movement of lactate from sites of activity either to inactive regions or to perivascular spaces of larger blood vessels [356–358] (see Fig. 15). Much of the lactate removed from the parenchyma via perivascular transport is likely to be removed from the brain along with CSF, though a proportion reaches lymph, possibly via the meninges, without first mixing with CSF. Lactate in CSF that leaves via the cribriform plate is delivered to the nasal mucosa from which it may return to blood either indirectly via lymph or directly by crossing peripheral capillary walls [85, 120, 125].16\nFig. 15 Lactate removal from the brain. Lactate produced within the brain can be effluxed via the blood–brain barrier or via perivascular routes. It may reach the latter locally near the site of its production or at more distant sites having been transferred between astrocytes via gap junctions\n(Diagram modified from Figure 7c in Gandhi et al. [358])\nIt remains puzzling why so much of the lactate produced within the brain during nerve activity appears to be removed rather than serving as fuel for oxidation in neurons as proposed in the astrocyte neuron lactate shuttle (ANLS) hypothesis (G. A. Dienel, personal communication). However, at least according to Dienel [345] the available evidence is that the oxygen consumption does not increase sufficiently during nerve activity for shuttling of lactate from astrocytes to neurons and further oxidative metabolism of lactate in neurons to be an important mechanism. Furthermore using expression of a genetically encoded NAD sensor that can be monitored in real time with cellular resolution, Diaz-Garcia et al. [346] have found in mice that nervous activity induces neural production rather than consumption of lactate. For an alternative view see e.g. 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