scholarly journals The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions

2020 ◽  
Vol 37 (7) ◽  
Author(s):  
Esmée Vendel ◽  
Vivi Rottschäfer ◽  
Elizabeth C.M. de Lange
Keyword(s):  
Brain Tissue ◽  
Network Model ◽  
Drug Exposure ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Drug Concentrations ◽  
Induced Changes ◽  
The Impact ◽  
The Brain ◽  
Unit Network

Abstract Purpose We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF). Methods The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF. The model includes the distribution of unbound drug within blood plasma, coupled with the distribution of drug within brain ECF and incorporates brain capillaryblood flow, passive paracellular and transcellular BBB transport, active BBB transport, brain ECF diffusion, brain ECF bulk flow, and specific and nonspecific brain tissue binding. All of these processes may change under disease conditions. Results We show that the simulated disease-induced changes in brain tissue characteristics significantly affect drug concentrations within the brain ECF. Conclusions We demonstrate that the 3D brain unit network model is an excellent tool to gain understanding in the interdependencies of the factors governing spatial-temporal drug concentrations within the brain ECF. Additionally, the model helps in predicting the spatial-temporal brain ECF concentrations of existing drugs, under both normal and disease conditions.

scholarly journals A 3D brain unit model to further improve prediction of local drug distribution within the brain

2019 ◽  
Author(s):  
Esmée Vendel ◽  
Vivi Rottschäfer ◽  
Elizabeth C. M. de Lange
Keyword(s):  
Extracellular Fluid ◽  
Drug Distribution ◽  
Drug Binding ◽  
Brain Capillaries ◽  
Drug Concentrations ◽  
Unit Model ◽  
Quantitative Understanding ◽  
The Impact ◽  
The Brain ◽  
Excellent Tool

AbstractThe development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and trancellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed.In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.Author summaryInsights on how a drug distributes within the brain over both time and space are still limited. Here, we develop a ‘3D brain unit model’ in order to understand the factors that control drug concentrations within a small piece of brain tissue, the 3D brain unit. In one 3D brain unit, the brain capillaries, which are the smallest blood vessels of the brain, surround the brain extracellular fluid (ECF). The blood-brain barrier (BBB) is located between the brain capillaries and the brain ECF. The model describes the impact of brain capillary blood flow, transport across the BBB, diffusion, flow and drug binding on the distribution of a drug within the brain ECF. We distinguish between free (unbound) drug and drug that is bound to binding sites within the brain. We show that all of the above mentioned factors affect drug concentrations within brain ECF in an interdependent manner. The 3D brain unit model that we have developed is an excellent tool to increase our understanding of how local drug concentrations within the brain ECF are affected by brain transport and binding processes.

scholarly journals Chemerin-induced macrophages pyroptosis in fetal brain tissue leads to cognitive disorder in offspring of diabetic dams

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Zhaoxia Liang ◽  
Luyang Han ◽  
Dianjianyi Sun ◽  
Yanmin Chen ◽  
Qi Wu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Brain Tissue ◽  
Abdominal Cavity ◽  
Behavioral Changes ◽  
Dependent Manner ◽  
Diabetes In Pregnancy ◽  
The Impact ◽  
The Brain ◽  
In Pregnancy ◽  
Brain Tissues

Abstract Background Chemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear. Methods A diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes. Results Chemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam’s offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams’ offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams. Conclusions Chemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.

scholarly journals Effect of hemostasis and electrosurgery on the development and evolution of brain tumor surgery in the late 19th and early 20th centuries

2005 ◽  
Vol 18 (4) ◽  
pp. 1-7 ◽  
Author(s):  
John R. Vender ◽  
Jason Miller ◽  
Andy Rekito ◽  
Dennis E. McDonnell
Keyword(s):  
Brain Tumor ◽  
Brain Tissue ◽  
Surgical Management ◽  
Tumor Surgery ◽  
Brain Tumor Surgery ◽  
The Impact ◽  
Neurological Surgeon ◽  
The Brain ◽  
Development And Evolution ◽  
Type Of Surgery

Hemostatic options available to the surgeon in the late 19th and early 20th centuries were limited. The surgical ligature was limited in value to the neurological surgeon because of the unique structural composition of brain tissue as well as the approaches and operating angles used in this type of surgery. In this manuscript the authors review the options available and the evolution of surgical hemostatic techniques and electrosurgery in the late 19th and early 20th centuries and the impact of these methods on the surgical management of tumors of the brain and its coverings.

scholarly journals Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Pooja Manchandani ◽  
Jian Zhou ◽  
Jessica T. Babic ◽  
Kimberly R. Ledesma ◽  
Luan D. Truong ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Drug Exposure ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Renal Tissue ◽  
Sprague Dawley ◽  
Electron Microscopic ◽  
Drug Concentrations ◽  
The Impact

ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.

scholarly journals Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar

2021 ◽  
Author(s):  
Jingu Lee ◽  
Joon-Goon Kim ◽  
Sujung Hong ◽  
Young Seo Kim ◽  
Soyeon Ahn ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Brain Tissue ◽  
Neuronal Death ◽  
Cellular Level ◽  
Intravital Imaging ◽  
Monoamine Oxidase B ◽  
Infarct Area ◽  
The Impact ◽  
The Brain

AbstractCerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage indicating blood-brain barrier (BBB) dysfunction. At day 5, edema disappeared with recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct. Oral administration of a reversible monoamine oxidase B inhibitor significantly decreased the astrocyte reactivity and fibrous scar formation. Our result suggests that astrocyte reactivity may be a key target to alleviate the impact of microinfarction.

Chemical targeting of voltage sensitive dyes to specific cells and molecules in the brain

2020 ◽  
Author(s):  
Tomas Fiala ◽  
Jihang Wang ◽  
Matthew Dunn ◽  
Peter Šebej ◽  
Se Joon Choi ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Brain Tissue ◽  
Fluorescent Dyes ◽  
Brain Slices ◽  
Brain Regions ◽  
Expression Levels ◽  
Specific Targeting ◽  
The Impact ◽  
Voltage Sensitive Dyes ◽  
The Brain

Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. These sensors, rendered highly lipophilic to anchor the conjugated pi-wire molecular framework in the membrane, offer several favorable functional parameters including fast response kinetics and high sensitivity to membrane potential changes. The impact of VSDs has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a non-genetic molecular platform for cell- and molecule-specific targeting of synthetic voltage sensitive dyes in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of voltage sensitive dyes by dynamic encapsulation, and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. We envision that modularity of our platform will enable its application to a variety of molecular targets and sensors, as well as lipophilic drugs and signaling modulators. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.

scholarly journals Material and Structural Modeling Aspects of Brain Tissue Deformation under Dynamic Loads

Materials ◽  
2019 ◽  
Vol 12 (2) ◽  
pp. 271 ◽  
Author(s):  
Monika Ratajczak ◽  
Mariusz Ptak ◽  
Leszek Chybowski ◽  
Katarzyna Gawdzińska ◽  
Romuald Będziński
Keyword(s):  
Brain Tissue ◽  
Human Subjects ◽  
Experimental Studies ◽  
Material Modeling ◽  
Geometrical Parameters ◽  
Dynamic Loading Conditions ◽  
Technological Improvements ◽  
The Impact ◽  
The Brain

The aim of this work was to assess the numerous approaches to structural and material modeling of brain tissue under dynamic loading conditions. The current technological improvements in material modeling have led to various approaches described in the literature. However, the methods used for the determination of the brain’s characteristics have not always been stated or clearly defined and material data are even more scattered. Thus, the research described in this paper explicitly underlines directions for the development of numerical brain models. An important element of this research is the development of a numerical model of the brain based on medical imaging methods. This approach allowed the authors to assess the changes in the mechanical and geometrical parameters of brain tissue caused by the impact of mechanical loads. The developed model was verified through comparison with experimental studies on post-mortem human subjects described in the literature, as well as through numerical tests. Based on the current research, the authors identified important aspects of the modeling of brain tissue that influence the assessment of the actual biomechanical response of the brain for dynamic analyses.

Chemical targeting of voltage sensitive dyes to specific cells and molecules in the brain

2020 ◽  
Author(s):  
Tomas Fiala ◽  
Jihang Wang ◽  
Matthew Dunn ◽  
Peter Šebej ◽  
Se Joon Choi ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Brain Tissue ◽  
Fluorescent Dyes ◽  
Brain Slices ◽  
Brain Regions ◽  
Expression Levels ◽  
Specific Targeting ◽  
The Impact ◽  
Voltage Sensitive Dyes ◽  
The Brain

Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. These sensors, rendered highly lipophilic to anchor the conjugated pi-wire molecular framework in the membrane, offer several favorable functional parameters including fast response kinetics and high sensitivity to membrane potential changes. The impact of VSDs has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a non-genetic molecular platform for cell- and molecule-specific targeting of synthetic voltage sensitive dyes in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of voltage sensitive dyes by dynamic encapsulation, and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. We envision that modularity of our platform will enable its application to a variety of molecular targets and sensors, as well as lipophilic drugs and signaling modulators. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.

The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

1992 ◽  
Vol 76 (4) ◽  
pp. 640-647 ◽  
Author(s):  
Stuart A. Grossman ◽  
Carla Reinhard ◽  
O. Michael Colvin ◽  
Mark Chasin ◽  
Robert Brundrett ◽  
...  
Keyword(s):  
New Zealand ◽  
Brain Tissue ◽  
Direct Injection ◽  
Normal Brain ◽  
Local Concentration ◽  
Content Type ◽  
Drug Concentrations ◽  
New Zealand White Rabbits ◽  
The Brain ◽  
Fine Print

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

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