Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans

1995 ◽  
Vol 268 (6) ◽  
pp. E1161-E1166 ◽  
Author(s):  
S. G. Hasselbalch ◽  
G. M. Knudsen ◽  
J. Jakobsen ◽  
L. P. Hageman ◽  
S. Holm ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Blood Brain Barrier ◽  
Plasma Glucose ◽  
Ketone Bodies ◽  
Brain Barrier ◽  
Affinity Constant ◽  
Indicator Method ◽  
Blood Brain ◽  
The Brain ◽  
Expected Increase

The blood-brain barrier (BBB) permeability for glucose and beta-hydroxybutyrate (beta-OHB) was studied by the intravenous double-indicator method in nine healthy subjects before and after 3.5 days of starvation. In fasting, mean arterial plasma glucose decreased and arterial concentration of beta-OHB increased, whereas cerebral blood flow remained unchanged. The permeability-surface area product for BBB glucose transport from blood to brain (PS1) increased by 55 +/- 31%, whereas no significant change in the permeability from brain back to blood (PS2) was found. PS1 for beta-OHB remained constant during starvation. The expected increase in PS1 due to the lower plasma glucose concentration was calculated to be 22% using previous estimates of maximal transport velocity and Michaelis-Menten affinity constant for glucose transport. The determined increase was thus 33% higher than the expected increase and can only be partially explained by the decrease in plasma glucose. It is concluded that a modest upregulation of glucose transport across the BBB takes place after starvation. Brain transport of beta-OHB did not decrease as expected from the largely increased beta-OHB arterial level. This might be interpreted as an increase in brain transport of beta-OHB, which could be caused by induction mechanisms, but the large nonsaturable component of beta-OHB transport makes such a conclusion difficult. However, beta-OHB blood concentration and beta-OHB influx into the brain increased by > 10 times. This implies that the influx of ketone bodies into the brain is largely determined by the amount of ketones present in the blood, and any condition in which ketonemia occurs will lead to an increased ketone influx.

Regional blood-brain barrier transport of ketone bodies in portacaval-shunted rats

1991 ◽  
Vol 261 (5) ◽  
pp. E647-E652 ◽  
Author(s):  
R. A. Hawkins ◽  
A. M. Mans
Keyword(s):  
Blood Brain Barrier ◽  
Ketone Bodies ◽  
Monocarboxylic Acid ◽  
Brain Barrier ◽  
Substantial Contribution ◽  
Sham Operation ◽  
Acid System ◽  
Portacaval Shunting ◽  
Blood Brain ◽  
The Brain

The permeability of the blood-brain barrier to ketone bodies, substrates of the monocarboxylic acid carrier, was measured in individual brain structures of control and portacaval-shunted rats. The measurements were made 5-7 wk after the shunt or sham operation by quantitative autoradiography. Portacaval shunting caused the permeability to ketone bodies to decrease throughout the brain by approximately 70%. There was a striking change in the transport pattern in the cerebral cortex; deeper cortical layers were affected more than superficial layers. Ketone body consumption by brain is limited by the transport capacity of the monocarboxylic acid system. Therefore, in portacaval-shunted rats the very low activity of this system makes it unlikely that ketone bodies can make a substantial contribution during situations such as fasting. Likewise, other substrates of the monocarboxylic acid system, e.g., lactate and pyruvate, will have greatly restricted access to the brain after portacaval shunting. If the carrier is symmetrical, another consequence will be that exit of endogenously produced lactate will be retarded.

scholarly journals Transport of D-Glucose and 2-Fluorodeoxyglucose across the Blood-Brain Barrier in Humans

1996 ◽  
Vol 16 (4) ◽  
pp. 659-666 ◽  
Author(s):  
Steen G. Hasselbalch ◽  
Gitte M. Knudsen ◽  
Søren Holm ◽  
L. Pinborg Hageman ◽  
Brunella Capaldo ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Initial Distribution ◽  
Brain Barrier ◽  
Transport Parameters ◽  
Indicator Method ◽  
Blood Brain ◽  
The Difference ◽  
Regional Cerebral Glucose Metabolism ◽  
The Brain

The deoxyglucose method for calculation of regional cerebral glucose metabolism by PET using 18F-2-fluoro-2-deoxy-d-glucose (FDG) requires knowledge of the lumped constant, which corrects for differences in the blood–brain barrier (BBB) transport and phosphorylation of FDG and glucose. The BBB transport rates of FDG and glucose have not previously been determined in humans. In the present study these transport rates were measured with the intravenous double-indicator method in 24 healthy subjects during normoglycemia (5.2 ± 0.7 m M). Nine subjects were restudied during moderate hypoglycemia (3.4 ± 0.4 m M) and five subjects were studied once during hyperglycemia (15.0 ± 0.7 m M). The global ratio between the unidirectional clearances of FDG and glucose (K1*/K1) was similar in normoglycemia (1.48 ± 0.22), moderate hypoglycemia (1.41 ± 0.23), and hyperglycemia (1.44 ± 0.20). This ratio is comparable to what has been obtained in rats. We argue that the global ratio is constant throughout the brain and may be applied for the regional determination of LC. We also determined the transport parameters of the two hexoses from brain back to blood and, assuming symmetrical transport across the BBB, we found evidence of a larger initial distribution volume of FDG in brain (0.329 ± 0.236) as compared with that of glucose (0.162 ± 0.098, p < 0.005). The difference can be explained by the very short experimental time, in which FDG may distribute both intra- and extracellularly, whereas glucose remains in a volume comparable to the interstitial fluid of the brain.

scholarly journals Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

2020 ◽  
Vol 21 (3) ◽  
pp. 934 ◽  
Author(s):  
Romain Versele ◽  
Mariangela Corsi ◽  
Andrea Fuso ◽  
Emmanuel Sevin ◽  
Rita Businaro ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ketone Bodies ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Therapeutic Approaches ◽  
Protein Levels ◽  
Blood Brain ◽  
Aβ Clearance ◽  
The Brain

Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

Characterization of alpha-keto acid transport across blood-brain barrier in rats

1983 ◽  
Vol 245 (3) ◽  
pp. E253-E260 ◽  
Author(s):  
A. R. Conn ◽  
D. I. Fell ◽  
R. D. Steele
Keyword(s):  
Blood Brain Barrier ◽  
Ketone Bodies ◽  
Reciprocal Inhibition ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Sprague Dawley ◽  
Monocarboxylic Acids ◽  
Blood Brain ◽  
Keto Acids ◽  
The Brain

The transport of keto acids, monocarboxylic acids, and ketone bodies was studied in barbiturate-anesthetized, adult male Sprague-Dawley rats. [1-14C]propionate and D-3-[3-14C]hydroxybutyrate were found to cross the blood-brain barrier with brain uptake indexes of 43.53 and 7.10%, respectively. Transport of both of these substrates was saturable, with the values of transport Km being 2.03 and 6.54 mM, respectively. A Ki of 0.68 mM was derived from competition data measuring the uptake of [1-14C]alpha-ketoisocaproate in the presence of unlabeled alpha-ketobutyrate. This finding and results from classical inhibition studies support competition for transport of keto acids for a common carrier. The brain uptake of [1-14C]propionate was significantly reduced by keto acids and ketone bodies and the transport of D-3-[3-14C]hydroxybutyrate was significantly inhibited by unlabeled monocarboxylic acids, keto acids, and acetoacetate. Evidence for competitive transport of alpha-keto acids, monocarboxylic acids, and ketone bodies is presented in the form of classical double-reciprocal inhibition plots and of labeled monocarboxylic acids and ketone bodies by an increasing concentration of unlabeled alpha-ketoisocaproate, the latter method yielding Ki values of 0.29 and 0.63 mM, respectively. The brain uptake of labeled propionate was inhibited by unlabeled D-3-hydroxybutyrate. A Ki of 6.43 mM, derived from this data, approximated the Km of transport of D-3-hydroxybutyrate, suggesting that ketone bodies and monocarboxylic acids compete for transport via the same carrier that is operative for keto acids.

scholarly journals Neurobarrier Coupling in the Brain: A Partner of Neurovascular and Neurometabolic Coupling?

2005 ◽  
Vol 25 (1) ◽  
pp. 2-16 ◽  
Author(s):  
Luc Leybaert
Keyword(s):  
Blood Flow ◽  
Glucose Transport ◽  
Blood Brain Barrier ◽  
Neural Tissue ◽  
Brain Barrier ◽  
Neuronal Activation ◽  
Transport Parameters ◽  
Blood Brain ◽  
Neurometabolic Coupling ◽  
The Brain

Neurovascular and neurometabolic coupling help the brain to maintain an appropriate energy flow to the neural tissue under conditions of increased neuronal activity. Both coupling phenomena provide us, in addition, with two macroscopically measurable parameters, blood flow and intermediate metabolite fluxes, that are used to dynamically image the functioning brain. The main energy substrate for the brain is glucose, which is metabolized by glycolysis and oxidative breakdown in both astrocytes and neurons. Neuronal activation triggers increased glucose consumption and glucose demand, with new glucose being brought in by stimulated blood flow and glucose transport over the blood-brain barrier. Glucose is shuttled over the barrier by the GLUT-1 transporter, which, like all transporter proteins, has a ceiling above which no further stimulation of the transport is possible. Blood-brain barrier glucose transport is generally accepted as a nonrate-limiting step but to prevent it from becoming rate-limiting under conditions of neuronal activation, it might be necessary for the transport parameters to be adapted to the increased glucose demand. It is proposed that the blood-brain barrier glucose transport parameters are dynamically adapted to the increased glucose needs of the neural tissue after activation according to a neurobarrier coupling scheme. This review presents neurobarrier coupling within the current knowledge on neurovascular and neurometabolic coupling, and considers arguments and evidence in support of this hypothesis.

scholarly journals Sleep-Related Brain Activation Does Not Increase the Permeability of the Blood-Brain Barrier to Glucose

2005 ◽  
Vol 25 (8) ◽  
pp. 990-997 ◽  
Author(s):  
Alessandro Silvani ◽  
Valentina Asti ◽  
Chiara Berteotti ◽  
Tijana Bojic ◽  
Tullia Cianci ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Rem Sleep ◽  
Brain Activation ◽  
Brain Barrier ◽  
Sleep State ◽  
Indicator Method ◽  
Quiet Wakefulness ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Brain

We compared blood-brain barrier (BBB) permeability to glucose between quiet wakefulness and rapid-eye-movement (REM) sleep to assess whether changes in BBB permeability play a role in coupling glucose supply to the physiologic metabolic needs of the brain. Male Sprague-Dawley rats were prepared with electrodes for wake-sleep state scoring and with arterial and venous catheters. Using the single-pass, dual-label indicator method, unidirectional glucose extraction by the brain and cerebral blood flow (CBF) were simultaneously measured during states of quiet wakefulness ( n = 12) or REM sleep ( n = 7). The product of BBB surface area and permeability to glucose (PS product) was computed in each state. During REM sleep, CBF significantly exceeded that during quiet wakefulness in all regions but the cerebellum, whereas the difference in the PS product between quiet wakefulness and REM sleep was not statistically significant in any brain region. In the brain as a whole, CBF significantly increased 29% from quiet wakefulness to REM sleep, while a nonsignificant 0.8% increase occurred in the PS product. During REM sleep, the increase in CBF indicates a higher rate of brain glucose consumption than in quiet wakefulness, given the tight flow-metabolism coupling in the brain. Therefore, these data show that modulation of BBB permeability to glucose is not a mechanism that provides ‘energy on demand’ during the physiologic brain activation characterising REM sleep.

Blood-brain barrier permeability measurements by double-indicator method using intravenous injection

1994 ◽  
Vol 266 (3) ◽  
pp. H987-H999 ◽  
Author(s):  
G. M. Knudsen ◽  
K. D. Pettigrew ◽  
C. S. Patlak ◽  
O. B. Paulson
Keyword(s):  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Brain Barrier ◽  
Output Curve ◽  
Indicator Method ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain

The double-indicator technique with intracarotid bolus injection is useful for the estimation of transfer rates across the human blood-brain barrier. A method using intravenous tracer injection is developed whereby the input is measured at a peripheral artery and the output is measured at the jugular vein. To correct for differences in the brain input of test and reference substances, a five-parameter Dirac impulse response for passage through the cerebrovascular bed is computed from the input and output of the reference substance. This response is then combined with a capillary model of the brain. This is then convoluted with the arterial input curve of the test substance to yield a theoretical test output curve, which is compared with the actual test output curve. On the basis of these two curves and an appropriate mathematical model for the brain, estimates of blood-brain barrier permeability are obtained. In the present study, the techniques are compared in 13 patients in whom alternating intracarotid and intravenous bolus injections were given. For D-glucose, the two techniques yielded similar results. This was also the case for L-phenylalanine, provided that the erythrocyte compartment was taken into account. Data obtained after intravenous injection of leucine and water yielded similar results compared with previous intracarotid data.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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