scholarly journals Mathematical Models of Blood-Brain Barrier Transport of Monoclonal Antibodies Targeting the Transferrin Receptor and the Insulin Receptor

2021 ◽  
Vol 14 (6) ◽  
pp. 535
Author(s):  
William M. Pardridge ◽  
Tom Chou
Keyword(s):  
Monoclonal Antibodies ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Plasma Concentrations ◽  
Mass Action ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Blood Brain

We develop and analyze mathematical models for receptor-mediated transcytosis of monoclonal antibodies (MAb) targeting the transferrin receptor (TfR) or the insulin receptor (IR), which are expressed at the blood-brain barrier (BBB). The mass-action kinetic model for both the TfR and IR antibodies were solved numerically to generate predictions for the concentrations of all species in all compartments considered. Using these models, we estimated the rates of MAb endocytosis into brain capillary endothelium, which forms the BBB in vivo, the rates of MAb exocytosis from the intra-endothelial compartment into brain extracellular space, and the rates of receptor recycling from the endothelial space back to the luminal endothelial plasma membrane. Our analysis highlights the optimal rates of MAb association with the targeted receptor. An important role of the endogenous ligand, transferrin (Tf) or insulin, in receptor-mediated-transport (RMT) of the associated MAb was found and was attributed to the five order magnitude difference between plasma concentrations of Tf (25,000 nM) and insulin (0.3 nM). Our modeling shows that the very high plasma concentration of Tf leads to only 5% of the endothelial TfR expressed on the luminal endothelial membrane.

scholarly journals Kinetics of Blood–Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor

2021 ◽  
Vol 15 (1) ◽  
pp. 3
Author(s):  
William M. Pardridge
Keyword(s):  
Fusion Protein ◽  
Mathematical Models ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Luminal Membrane ◽  
Blood Brain ◽  
Kinetics Of ◽  
The Brain

Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.

Abstract 32: Exercise Training Corrects Blood-brain Barrier Dysfunction Within Preautonomic Areas Of Spontaneously Hypertensive Rats By Normalizing The Augmented Transcytosis

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Vanessa B Candido ◽  
Alexandre Ceroni ◽  
Alison Colquhoun ◽  
Lisete C Michelini
Keyword(s):  
Exercise Training ◽  
Blood Brain Barrier ◽  
Autonomic Control ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Pulse Interval ◽  
Barrier Dysfunction ◽  
Spontaneously Hypertensive ◽  
Blood Brain ◽  
Spontaneous Baroreflex

Introduction: Besides intense neuro-hormonal activation, hypertension is accompanied by blood-brain barrier (BBB) dysfunction within preautonomic areas and marked autonomic imbalance. We showed previously that exercise training (T) corrected both increased BBB leakage and autonomic dysfunction. There is no information on the mechanism(s) conditioning the normalization of BBB function Hypothesis: We hypothesized that T could modify the transcytosis and/or the paracellular transport across the capillary endothelium Methods: SHR and Wistar rats allocated to T (55% maximal capacity) or sedentary (S) protocols were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (fluorescent Rhodamine-70kDa+FITC-10kDa dyes given ia ). To analyze hypertension- and T-induced BBB changes, paraventricular hypothalamic nuclei (PVN) was harvested and processed for immunofluorescence and transmission electron microscopy Results: SHR-S vs Wistar-S exhibited augmented SAP and reduced pulse interval (PI) variability, decreased spontaneous baroreflex sensitivity (BrS), increased both PVN BBB leakage (11.4±0.6 vs 3.48 %area) and transcytosis (8.1±1.2 vs 4.8±0.8 vesicles/capillary) but no change in tight junctions’expression (TJ, number/capillary). SHR-T showed a near normal autonomic control, resting bradycardia and a partial AP reduction (-9%) accompanied by normalization of both BBB leakage (3.6±1.5 %area) and transcytosis (3.8±0.7 vesicles/capillary), and increased TJs’ extension (60% occupancy of capillary borders) without changing its expression. Hypertension- and T-induced transcytosis changes were confirmed by caveolin-1 immunofluorescence (SHR-S=139±11, Wistar-S=86±8, SHR-T=81±6 arbitrary units). There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=1.77x -3.46, r 2 =0.722, P<0.001) and BBB leakage x SAP variability (Y=2.30x +16.6, r 2 =0.246, P<0.001) Conclusions: PVN BBB dysfunction in hypertension is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates SHR’s autonomic control by normalizing transcytosis, with an additional TJs structure improvement

scholarly journals The Presence of Caffeic Acid in Cerebrospinal Fluid: Evidence That Dietary Polyphenols Can Cross the Blood-Brain Barrier in Humans

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1531 ◽  
Author(s):  
Izabela Grabska-Kobylecka ◽  
Justyna Kaczmarek-Bak ◽  
Malgorzata Figlus ◽  
Anna Prymont-Przyminska ◽  
Anna Zwolinska ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Caffeic Acid ◽  
Blood Brain Barrier ◽  
Solid Phase ◽  
Plasma Concentrations ◽  
Brain Barrier ◽  
Facilitated Diffusion ◽  
Dietary Polyphenols ◽  
Brain Functions ◽  
Blood Brain

Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brain functions, improving memory and cognition in humans. Direct activity of ingested phenolics on brain neurons may be one of plausible mechanisms explaining these data. This also suggests that some phenolics can cross the blood-brain barrier and be present in the brain or cerebrospinal fluid. We measured 12 phenolics (a combination of the solid-phase extraction technique with high-performance liquid chromatography) in cerebrospinal fluid and matched plasma samples from 28 patients undergoing diagnostic lumbar puncture due to neurological disorders. Homovanillic acid, 3-hydroxyphenyl acetic acid and caffeic acid were detectable in cerebrospinal fluid reaching concentrations (median; interquartile range) 0.18; 0.14 µmol/L, 4.35; 7.36 µmol/L and 0.02; 0.01 µmol/L, respectively. Plasma concentrations of caffeic acid (0.03; 0.01 µmol/L) did not correlate with those in cerebrospinal fluid (ρ = −0.109, p = 0.58). Because food (fruits and vegetables) is the only source of caffeic acid in human body fluids, our results indicate that the same dietary phenolics can cross blood-brain barrier in humans, and that transportation of caffeic acid through this barrier is not the result of simple or facilitated diffusion.

scholarly journals The pericyte–glia interface at the blood–brain barrier

2018 ◽  
Vol 132 (3) ◽  
pp. 361-374 ◽  
Author(s):  
Patrizia Giannoni ◽  
Jerome Badaut ◽  
Cyril Dargazanli ◽  
Alexis Fayd’Herbe De Maudave ◽  
Wendy Klement ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Glial Cells ◽  
Outer Wall ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Brain Capillary ◽  
Multicellular Structure ◽  
Blood Brain ◽  
Acute Insult ◽  
The Brain

The cerebrovasculature is a multicellular structure with varying rheological and permeability properties. The outer wall of the brain capillary endothelium is enclosed by pericytes and astrocyte end feet, anatomically assembled to guarantee barrier functions. We, here, focus on the pericyte modifications occurring in disease conditions, reviewing evidence supporting the interplay amongst pericytes, the endothelium, and glial cells in health and pathology. Deconstruction and reactivity of pericytes and glial cells around the capillary endothelium occur in response to traumatic brain injury, epilepsy, and neurodegenerative disorders, impacting vascular permeability and participating in neuroinflammation. As this represents a growing field of research, addressing the multicellular reorganization occurring at the outer wall of the blood-brain barrier (BBB) in response to an acute insult or a chronic disease could disclose novel disease mechanisms and therapeutic targets.

Transferrin Receptor-Mediated Uptake at the Blood–Brain Barrier Is Not Impaired by Alzheimer’s Disease Neuropathology

2019 ◽  
Vol 16 (2) ◽  
pp. 583-594 ◽  
Author(s):  
Philippe Bourassa ◽  
Wael Alata ◽  
Cyntia Tremblay ◽  
Sarah Paris-Robidas ◽  
Frédéric Calon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Transferrin Receptor ◽  
Brain Barrier ◽  
Blood Brain
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