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 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.

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.

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.

Ammonia selectively stimulates neutral amino acid transport across blood-brain barrier

1983 ◽  
Vol 245 (1) ◽  
pp. C74-C77 ◽  
Author(s):  
A. M. Mans ◽  
J. F. Biebuyck ◽  
R. A. Hawkins
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Monocarboxylic Acid ◽  
Basic Amino Acid ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Transport Systems ◽  
Portacaval Anastomosis ◽  
Portacaval Shunting ◽  
Blood Brain

The response to increased blood NH4+ of three blood-brain barrier transport systems, which are altered after portacaval anastomosis, was studied. NH4+ acetate was infused for 4 or 22 h to raise blood and brain NH4+, and brain glutamine, to levels similar to those observed after portacaval anastomosis. While brain glutamine content was much higher (16–20 mumol/g) than normal (6 mumol/g) at both times, the permeability of the blood-brain barrier to the neutral amino acid [14C]tryptophan was greater only after 22 h of infusion. After discontinuing the infusion for 5 h, tryptophan transport returned to normal, whereas brain glutamine remained elevated (13 mumol/g). Thus there seemed to be no relationship between the rate of transport and glutamine content. The permeability to [14C]sucrose was unaltered, showing that the integrity of the blood-brain barrier was maintained. Other changes that are characteristic of portacaval shunting, such as decreased basic amino acid ([14C]lysine) and monocarboxylic acid (3-[14C]hydroxybutyrate) transport, were not reproduced by 22 h of infusion. The results demonstrated that the continued presence of NH4+ could be responsible for the change in at least one of the transport systems that are affected by portacaval shunting.

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.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals Probable Causes of Alzheimer’s Disease

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lactic Acid ◽  
Blood Brain Barrier ◽  
Transient Receptor Potential ◽  
Brain Barrier ◽  
Folate Intake ◽  
Blood Brain ◽  
Age Related ◽  
The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

scholarly journals Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 909
Author(s):  
Yurii A. Zolotarev ◽  
Vladimir A. Mitkevich ◽  
Stanislav I. Shram ◽  
Alexei A. Adzhubei ◽  
Anna P. Tolstova ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Laboratory Animals ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Bolus Administration ◽  
Blood Brain ◽  
The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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