TRANSPORT OF METABOLIC SUBSTRATES THROUGH THE BLOOD‐BRAIN BARRIER<sup>1</sup>

Pardridge, William M.; Oldendorf, William H.

doi:10.1111/j.1471-4159.1977.tb07702.x

Cited by 513 publications

(218 citation statements)

References 95 publications

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“…Due to the high energy -demand of the brain, the abundance of GLUT1 at the microvasculature is high, relative to other transporters, which enables rates of glycolysis in the brain that are over 100-fold greater than rates of amino-acid incorporation into brain proteins. 83 However, due to the demand of carriers, the process of carrier mediated transport of a substance across the BBB is saturable.…”

Section: Mechanism Of Bbb Crossing By Endogenous Substancesmentioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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Section: Mechanism Of Bbb Crossing By Endogenous Substancesmentioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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“…A vast array of experimental data has been accumulated over the years, indicating that in vitro lactate is an essential energy substrate for synaptic transmission and can adequately maintain synaptic activity even in the absence of glucose (Schurr et al 1988(Schurr et al , 1999Izumi et al 1997). In vivo, lactate is not an adequate substrate since it crosses only marginally the blood^brain barrier (Pardridge & Oldendorf 1977); however, if formed within the brain parenchyma through the mechanism described above (¢gure 2b), or if applied to in vitro preparations, lactate may in fact be consumed preferentially to glucose, particularly during periods of intense activity (Larrabee 1995).…”

Section: Synaptically Released Glutamate Triggers Glucose Use In Astrmentioning

confidence: 99%

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Magistretti¹,

Pellerin²

1999

Phil. Trans. R. Soc. Lond. B

663

458

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Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood £ow and energy metabolism. Positron emission tomography (PET) signals detect blood £ow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identi¢es the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic £uxes in puri¢ed preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identi¢ed the neurotransmitter glutamate and astrocytes, a speci¢c type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This e¡ect is mediated by speci¢c glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na + . This Na + -dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na + /K + -ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na + ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one`turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule....

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“…7, No.1, 1987 There are at least eight distinctive carrier systems that facilitate the trans endothelial trans port of metabolic substrates between blood and brain (Pardridge and Oldendorf, 1977). Although in flux from blood to brain has been most easily studied and quantified, the available data generally suggest that some of the involved carrier systems have a capacity for bidirectional transport.…”

Section: Figmentioning

confidence: 99%

“…Although in flux from blood to brain has been most easily studied and quantified, the available data generally suggest that some of the involved carrier systems have a capacity for bidirectional transport. The hexose carrier is completely bidirectional and sym metrical for glucose (Pard ridge and Oldendorf, 1975), whereas the monocarboxylic acid carrier for lactate, although bidirectional, is asymmetric, with a threefold larger efflux than influx rate (Pardridge and Oldendorf, 1977). The carrier for 5-HIAA and HVA appears to be totally asymmetric, as carrier mediated movement of these metabolites occurs only from brain to blood (Yuwiler et aI., 1982).…”

Section: Figmentioning

confidence: 99%

“…By way of example, Pardridge and Oldendorf (1977) have suggested that the restricted ability of the monocarboxylic acid carrier to remove lactate from the brain may be a basis for the selective vulnera bility of the brain to anoxia. By use of probenecid with various levels of hypoxia and ischemia, it may be possible to produce larger accumulations of lac tate or more prolonged exposures of brain to ele vated lactate levels and to thus test this and other theories that attribute a major pathogenetic role to lactacidosis in ischemic brain damage (see Plum, 1983).…”

Section: Figmentioning

confidence: 99%

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Effect of Probenecid on Cerebral and Cisternal Cerebrospinal Fluid Lactate Content

MacMillan

1987

J Cereb Blood Flow Metab

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Summary: In this study, the cisternal CSF contents of lactate and glucose were sequentially measured in free moving rats that had been administered probenecid, 200 mg/kg-I, drug diluent, or no injections. In animals re ceiving either no injections or injections of drug diluent, CSF lactate and glucose were constant over a 6-h period (93-106% of control), whereas rats receiving probenecid showed increased lactate at 1 and 2 h (170 and 125% con trol, respectively) and increased glucose at 1, 2, and 3 h (169, 141 and 129% control, respectively). Cerebral cortex content of energy metabolites and lactate and blood lactate levels were statistically unaltered at 0.5-6 h exposure to probenecid, whereas cerebral and blood glu cose contents were increased after I and 2 h exposure to probenecid. Rats exposed to 5% O2 and probenecid for Probenecid [P-(dipropylsulfamoyl) benzoic acid] competitively inhibits the transport of 5-hydroxyin dole acetic acid (5-HIAA) and homo vanillic acid (HVA) from brain to blood (Guldberg et aI., 1966;Korf and Van Praag, 1971; Faull et aI., 1981). Avail able kinetic data suggest that the predominant sites for this organic acid transport system are the choroid plexus (Forn, 1972) and cortical-spinal subarachnoid space and their respective vascular structures (Wolfson et aI., 1974; Burns et aI., 1976; Van Der Poel et aI., 1977). Pardridge et ai. (1975) have presented data that indicates that probenecid also competitively inhibits the capillary endothelial monocarboxylic acid carrier. This has been con firmed by Yuwiler et al. (1982), who demonstrated that probenecid inhibits the uptake of short-chain Received April 7, 1986; revised September 16, 1986. 118 0.5 h showed a statistically higher CSF lactate at 0.5 and 1.5 h reoxygenation (169 and 168% control, respectively). A similar effect was also seen in rats exposed to 5% O2 and the 5-hydroxyindoleacetic acid (5-HIAA) transport inhibitor Na divalproate. The results suggested that the increase in CSF glucose was secondary to a probenecid induced elevation of blood glucose, whereas the increase in CSF lactate seemed to be secondary to a reduced rate of efflux of lactate from the CSF. It is suggested that it may be possible to increase the CSF lactate content by mechanisms that are independent of direct effects on the processes of cerebral energy metabolism. Key Words: Probenecid-CSF lactate-Cerebral energy metabolism -Blood-brain transport.monocarboxylic acids, such as lactate and proprio nate, from blood to brain. As the steady-state efflux rate of lactate from brain is estimated to be about 3 times that of influx (Pardridge et aI., 1975), it is pos sible to postulate on the basis of the above data that probenecid administration could result in an in crease in the lactate content of the cerebrospinal (CSF) and extracellular fluid of the brain. The ob jective of the present study was to test this hy pothesis by direct measurement of the cisternal CSF lactate content of rats administered proben ecid. In addition, the cisternal CSF glucose conten...

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TRANSPORT OF METABOLIC SUBSTRATES THROUGH THE BLOOD‐BRAIN BARRIER¹

Cited by 513 publications

References 95 publications

Nanoparticle transport across the blood brain barrier

Nanoparticle transport across the blood brain barrier

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Effect of Probenecid on Cerebral and Cisternal Cerebrospinal Fluid Lactate Content

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TRANSPORT OF METABOLIC SUBSTRATES THROUGH THE BLOOD‐BRAIN BARRIER1

Cited by 513 publications

References 95 publications

Nanoparticle transport across the blood brain barrier

Nanoparticle transport across the blood brain barrier

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Effect of Probenecid on Cerebral and Cisternal Cerebrospinal Fluid Lactate Content

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Product

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TRANSPORT OF METABOLIC SUBSTRATES THROUGH THE BLOOD‐BRAIN BARRIER¹