APPARENT IN VIVO ACETYLCHOLINE TURNOVER RATE IN WHOLE MOUSE BRAIN: EVIDENCE FOR A TWO COMPARTMENT MODEL BY TWO INDEPENDENT KINETIC ANALYSES

1979 ◽  
Vol 32 (5) ◽  
pp. 1417-1422 ◽  
Author(s):  
Frank J. Vocci ◽  
Michael J. Karbowski ◽  
William L. Dewey
Keyword(s):  
Mouse Brain ◽  
Turnover Rate ◽  
Compartment Model ◽  
Two Compartment Model ◽  
Acetylcholine Turnover

scholarly journals Assessment of Metabolic Fluxes in the Mouse Brain in Vivo Using 1H-[13C] NMR Spectroscopy at 14.1 Tesla

2015 ◽  
Vol 35 (5) ◽  
pp. 759-765 ◽  
Author(s):  
Lijing Xin ◽  
Bernard Lanz ◽  
gxia Lei ◽  
Rolf Gruetter
Keyword(s):  
Mouse Models ◽  
Mouse Brain ◽  
Conversion Rate ◽  
Tca Cycle ◽  
Compartment Model ◽  
13C Nmr Spectroscopy ◽  
Resonance Spectroscopy ◽  
Metabolic Fluxes ◽  
Short Echo Time

13C magnetic resonance spectroscopy (MRS) combined with the administration of 13C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity 1H-[13C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-13C6] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the 13C turnover curves of glutamate C4, glutamine C4, glutamate+glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit 13C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux VTCA (1.05 ± 0.04 μmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate Vx (0.48 ± 0.02 μmol/g per minute), the glutamate-glutamine exchange rate Vgln (0.20 ± 0.02 μmol/g per minute), the pyruvate dilution factor Kdil (0.82 ± 0.01), and the ratio for the lactate conversion rate and the alanine conversion rate VLac/ VAla (10 ± 2). This study opens the prospect of studying transgenic mouse models of brain pathologies.

Rapid changes in hepatic glucose output after a pulse of growth hormone in dogs

1984 ◽  
Vol 246 (1) ◽  
pp. E14-E20
Author(s):  
P. Vaitkus ◽  
A. Sirek ◽  
K. H. Norwich ◽  
O. V. Sirek ◽  
R. H. Unger ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Venous Blood ◽  
Compartment Model ◽  
Glucose Turnover ◽  
Base Line ◽  
Indwelling Catheter ◽  
Two Compartment Model ◽  
Portal Venous Blood ◽  
Glucose Output

In response to a single intravenous injection of bovine growth hormone (GH, 100 micrograms/kg) the non-steady-state turnover of glucose, as well as portal levels of insulin (IRI), glucagon (IRG), somatostatin (SRIF), and glucose were determined in normal conscious dogs. Using the two-compartment model validated to calculate rapid turnover changes and tracer infusion methods, the rate of hepatic output of glucose [Ra(t)] was found to be increased, reaching a maximum of 224 mg/min, 7.4 times the basal rate, 4 min after injection of GH. Ra(t) returned to its basal level 35 min later in a damped oscillatory manner. Hormone determinations were carried out in portal venous blood drawn every 2 min for 2 h from an indwelling catheter. IRG peaked 2 min after GH injection and levels of IRI, SRIF, and glucose peaked between 4 and 8 min. Hormone concentrations returned to normal, i.e., were oscillating around base-line levels, about 30 min after GH. These experiments demonstrate for the first time in vivo that a pulse of GH causes transient changes of glucose turnover and measurable alterations of the hormonal homeostasis in the splanchnic area.

BIOSYNTHESIS OF C19 STEROIDS FROM 4-14C-CHOLESTEROL AND 7-3H-PREGNENOLONE IN VIVO: CONSIDERATION OF NEW PATHWAYS

1962 ◽  
Vol 40 (2) ◽  
pp. 188-202 ◽  
Author(s):  
Shlomo Burstein ◽  
Ralph I. Dorfman
Keyword(s):  
Adrenal Adenoma ◽  
Mevalonic Acid ◽  
Compartment Model ◽  
Side Chain ◽  
Partition Chromatography ◽  
Steroid Nucleus ◽  
Single Intravenous Injection ◽  
Two Compartment Model ◽  
Specific Activities

ABSTRACT 3H and 14C specific activities of dehydroepiandrosterone, androsterone, 3α-hydroxy-5β-androstan-17-one and 3α-hydroxy-5α-androst-16-ene (without dilution) have been determined following a single intravenous injection of 4-14C-cholesterol and 7α-3H-pregnenolone to a virilized woman with an adrenal adenoma and massive dehydroepiandrosterone excretion. Assuming a one compartment model, or a two compartment model in which the injected radioactivity enters the compartment in which the precursor is secreted exclusively, a new pathway by which dehydroepiandrosterone is formed from cholesterol not through pregnenolone and possibly by cleavage of the side chain C-17 and C-20 is indicated. Analysis of the data by a model in which pregnenolone is secreted into two separate compartments in which progesterone and dehydroepiandrosterone are made, respectively, would explain the findings without necessitating the assumption of a new pathway. 3α-Hydroxy-5α-androst-16-ene was isolated from urine following incubation with β-glucuronidase and partition chromatography on celite suggesting that this steroid is a genuine natural product as surmised by Prelog & Ruzicka (1944) and Brooksbank & Haslewood (1950). 2-14C-Mevalonate was shown to give rise to C19 steroids which is the first in vivo demonstration that mevalonic acid is a precursor of the steroid nucleus in man.

Pentobarbital and in vivo turnover rate of acetylcholine in mouse brain and in regions of rat brain

1975 ◽  
Vol 7 (1) ◽  
pp. 81-94 ◽  
Author(s):  
M. Trabucchi ◽  
D.L. Cheney ◽  
G. Racagni ◽  
E. Costa
Keyword(s):  
Rat Brain ◽  
Mouse Brain ◽  
Turnover Rate

Determination of digesta fill and passage rate from nonabsorbed particulate phase markers using the single dosing method

1989 ◽  
Vol 67 (2) ◽  
pp. 488-494 ◽  
Author(s):  
D. F. Holleman ◽  
R. G. White
Keyword(s):  
Compartment Model ◽  
Time Dependent ◽  
Passage Rate ◽  
Fecal Output ◽  
Two Compartment Model ◽  
Significant Difference ◽  
Single Marker ◽  
Dependent Model ◽  
Digesta Passage

A method is given for analyzing particulate digestive marker data in terms of digesta fill, fecal output, and digesta passage times. The method applies the Stewart – Hamilton Principle to data obtained from a single marker dosing followed by feces sampling; it assumes steady-state conditions for the digesta, but makes no assumptions concerning compartmentalization of digesta. Data analyses are presented for an experiment with sheep in which a particle phase marker, cerium-141 chloride, was used. The estimate of fecal output obtained was 1.8 ± 2.2% (mean percent difference ± SE) greater than the actual fecal output; the in vivo estimate of total digesta fill was 3.3 ± 3.4% less than measured digesta fill. For comparison, the present data were also analyzed using two established compartment modeling approaches, namely a time-independent and a time-dependent two-compartment model. The only significant difference between the estimated parameters as obtained from the Stewart – Hamilton method and the compartmental models was a significantly shorter transit time as estimated by the time-dependent model.

Single Dose Administration of rFVIIa and NN1731 in Two Hemophilia A Dogs.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3144-3144 ◽  
Author(s):  
Mirella Ezban ◽  
Lone Frost ◽  
Dorthe Viuff ◽  
Judi Møss ◽  
Mark Kloos ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Ex Vivo ◽  
Compartment Model ◽  
Initial Distribution ◽  
Coagulation Assays ◽  
Two Compartment Model ◽  
Dose Study ◽  
Related Proteins

Abstract Introduction: The objective of this pilot study was to evaluate and compare the pharmacokinetic and pharmacodynamic (PK/PD) profile of rFVIIa and NN1731 in two hemophilia A dogs. In addition, it was the aim to evaluate the use of TEG for monitoring rFVIIa/NN1731 activity after in vivo administration and to compare with ex vivo spiking data from a previous study. NN1731 is a new rFVIIa analoge with enhanced activity (Allen et al. Arterioscler. Thromb. Vasc. Biol.2007;27:683–689). In hemophilia patients as well as hemophilia dogs the clot formation is impaired and reflected in coagulation assays such as thromboelastography (TEG) and APTT. The choice of hemophilia dogs is based upon the knowledge that the pharmacokinetics of human coagulations factors (FVIII, FIX and rFVIIa) as well as the effective dose is similar to that in humans. In normal dogs, it is not possible to evaluate the effect of these procoagulant proteins in coagulation assays as no impaired clotting is observed. Methods: rFVIIa and NN1731 (280 μg/kg IV) were administered to two hemophilia dogs on separate days and plasma samples collected at different time points. FVIIa activity was measured by the FVIIa clot assay and values were used for pharmacokinetic assessment. The same pharmacokinetic models, a non-compartmental method and a two compartment model, respectively, were used as was the case in the First Human Dosing (FHD) trial of NN1731 (NN1731–1639). Analysis of PD markers in dogs included: APTT, PT and whole blood thromboelastography analysis, recently developed for use in hemophilia dogs. Results: Based on the FVIIa activity profile in the two dogs it was observed that the values obtained at the first time point (C5 min), were higher after treatment with NN1731 than after rFVIIa. All activity based assays including TEG demonstrated that NN1731 was cleared faster than rFVIIa., FVIIa activity (FVIIa clot assay), showed a rapid initial distribution and/or elimination of FVIIa activity (t1/2α:0.3 h) followed by a less rapid elimination phase (t½β:3.5 h). Similar profile and values were obtained for NN1731 in the FHD dose study (J. Møss et al, ISTH, 2007) Conclusions: This study indicates that in hemophilia A dogs, NN1731 and rFVIIa have distinct PK profiles and very similar to what is observed in man. All activity assays show the same qualitative profile, the FVIIa clot assay being the most sensitive assay. The TEG data obtained in vivo are in accordance with the values obtained after in vitro spiking. The data support the use of hemophilia dogs for evaluating the pharmacokinetic and pharmacodynamic profiles of FVIIa related proteins.

scholarly journals Differentiation of Radioligand Delivery and Binding in the Brain: Validation of a Two-Compartment Model for [11C]Flumazenil

1991 ◽  
Vol 11 (5) ◽  
pp. 745-752 ◽  
Author(s):  
Vjera A. Holthoff ◽  
Robert A. Koeppe ◽  
Kirk A. Frey ◽  
Avram H. Paradise ◽  
David E. Kuhl
Keyword(s):  
Benzodiazepine Receptor ◽  
Occipital Cortex ◽  
Compartment Model ◽  
Stable Measure ◽  
Intravenous Injections ◽  
Audiovisual Stimulation ◽  
Positron Emission ◽  
Two Compartment Model ◽  
Tracer Kinetic

We recently developed a two-compartment, two-parameter tracer kinetic model to estimate the in vivo ligand transport rate ( K1) and distribution volume (DV) for the benzodiazepine antagonist [11C]flumazenil (FMZ) as measured by positron emission tomography (PET). The aim of the present study was to validate that this simplified model provides a stable measure of regional benzodiazepine receptor availability even when ligand delivery is altered. Six young normal volunteers underwent two PET studies subsequent to intravenous injections of [11C]FMZ. Each FMZ study was immediately preceded by measurements of CBF following injection of [15O]water. One set of scans (water/FMZ) was acquired under resting conditions and the other set during audiovisual stimulation. Six additional volunteers underwent two FMZ studies under identical resting conditions. Parametric images were analyzed and a comparison of test-retest studies in the stimulation group revealed a significant increase of CBF and K1 of FMZ in the occipital cortex evoked by visual activation, whereas no regional changes were noted for the DV of FMZ. No significant changes were noted for either K1 or DV of FMZ when comparing studies in the rest-rest setting. The results indicate that the use of a simple two-compartment model for the tracer kinetic analysis of [11C]FMZ makes it possible to separate high-affinity binding from altered radioligand delivery to the human brain.

scholarly journals Robust Multi-TE ASL-Based Blood–Brain Barrier Integrity Measurements

2021 ◽  
Vol 15 ◽  
Author(s):  
Amnah Mahroo ◽  
Mareike Alicja Buck ◽  
Jörn Huber ◽  
Nora-Josefin Breutigam ◽  
Henk J. M. M. Mutsaerts ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Transit Time ◽  
Grey Matter ◽  
Compartment Model ◽  
Brain Barrier ◽  
Extended Model ◽  
Blood Brain ◽  
Two Compartment Model ◽  
Bbb Permeability

Multiple echo-time arterial spin labelling (multi-TE ASL) offers estimation of blood–tissue exchange dynamics by probing the T2 relaxation of the labelled spins. In this study, we provide a recipe for robust assessment of exchange time (Texch) as a proxy measure of blood–brain barrier (BBB) integrity based on a test-retest analysis. This includes a novel scan protocol and an extension of the two-compartment model with an “intra-voxel transit time” (ITT) to address tissue transit effects. With the extended model, we intend to separate the underlying two distinct mechanisms of tissue transit and exchange. The performance of the extended model in comparison with the two-compartment model was evaluated in simulations. Multi-TE ASL sequence with two different bolus durations was used to acquire in vivo data (n = 10). Cerebral blood flow (CBF), arterial transit time (ATT) and Texch were fitted with the two models, and mean grey matter values were compared. Additionally, the extended model also extracted ITT parameter. The test-retest reliability of Texch was assessed for intra-session, inter-session and inter-visit pairs of measurements. Intra-class correlation coefficient (ICC) and within-subject coefficient of variance (CoV) for grey matter were computed to assess the precision of the method. Mean grey matter Texch and ITT values were found to be 227.9 ± 37.9 ms and 310.3 ± 52.9 ms, respectively. Texch estimated by the extended model was 32.6 ± 5.9% lower than the two-compartment model. A significant ICC was observed for all three measures of Texch reliability (P < 0.05). Texch intra-session CoV, inter-session CoV and inter-visit CoV were found to be 6.6%, 7.9%, and 8.4%, respectively. With the described improvements addressing intra-voxel transit effects, multi-TE ASL shows good reproducibility as a non-invasive measure of BBB permeability. These findings offer an encouraging step forward to apply this potential BBB permeability biomarker in clinical research.

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