Use of Cassette Dosing Approach to Examine the Effects of P-Glycoprotein on the Brain and Cerebrospinal Fluid Concentrations in Wild-Type and P-Glycoprotein Knockout Rats

2014 ◽  
Vol 42 (4) ◽  
pp. 482-491 ◽  
Author(s):  
Xingrong Liu ◽  
Jonathan Cheong ◽  
Xiao Ding ◽  
Gauri Deshmukh
Keyword(s):  
Cerebrospinal Fluid ◽  
Wild Type ◽  
P Glycoprotein ◽  
The Brain ◽  
Cassette Dosing

scholarly journals Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 2982 ◽  
Author(s):  
Gil Yong Park ◽  
Angelo Jamerlan ◽  
Kyu Hwan Shim ◽  
Seong Soo A. An
Keyword(s):  
Cerebrospinal Fluid ◽  
Genetic Mutations ◽  
Hormone Binding ◽  
Wild Type ◽  
Autonomic Motor ◽  
Hormone Binding Protein ◽  
The Brain ◽  
Tetrameric Form

Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.

Inhibition of P-glycoprotein Activity at the Primate Blood-Brain Barrier Increases the Distribution of Nelfinavir into the Brain but Not into the Cerebrospinal Fluid

2007 ◽  
Vol 35 (9) ◽  
pp. 1459-1462 ◽  
Author(s):  
Amal Kaddoumi ◽  
Sung-Up Choi ◽  
Loren Kinman ◽  
Dale Whittington ◽  
Che-Chung Tsai ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Brain

scholarly journals Gender Effects on Plasma and Brain Copper

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Joseph F. Quinn ◽  
Christopher Harris ◽  
Jeffrey A. Kaye ◽  
Babett Lind ◽  
Raina Carter ◽  
...  
Keyword(s):  
Gender Differences ◽  
Cerebrospinal Fluid ◽  
Human Subjects ◽  
Serum Copper ◽  
Gender Effects ◽  
Wild Type ◽  
Copper Status ◽  
Plasma Copper ◽  
Healthy Control ◽  
The Brain

The effect of gender on systemic and brain levels of copper is relatively understudied. We examined gender effects in mice and human subjects. We observed a trend to higher serum copper levels in female compared to male LaFerla “triple transgenic” (1399±233versus804±436 ng/mL,P=0.06) mice, and significantly higher brain copper levels in female- versus male wild-type mice (5.2±0.2versus4.18±0.3 ng/mg wet wt,P=0.03). Plasma copper was significantly correlated with brain copper in mice (R2 = 0.218;P=0.038). Among human subjects with AD, both plasma copper (1284±118versus853±81 ng/mL,P=0.005) and cerebrospinal fluid copper (12.8±1versus10.4±0.7 ng/mL,P=0.01) were elevated in women compared to men. Among healthy control subjects, plasma copper (1008±51versus836±41 ng/mL;P=0.01) was higher in women than in men, but there was no difference in cerebrospinal fluid copper. We conclude that gender differences in copper status may influence copper-mediated pathological events in the brain.

scholarly journals Distribution of Suramin, an Antitrypanosomal Drug, across the Blood-Brain and Blood-Cerebrospinal Fluid Interfaces in Wild-Type and P-Glycoprotein Transporter-Deficient Mice

2007 ◽  
Vol 51 (9) ◽  
pp. 3136-3146 ◽  
Author(s):  
Lisa Sanderson ◽  
Adil Khan ◽  
Sarah Thomas
Keyword(s):  
Choroid Plexus ◽  
Brain Perfusion ◽  
Brain Parenchyma ◽  
Sleeping Sickness ◽  
New Drugs ◽  
Wild Type ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Targeted Mutation ◽  
The Brain

ABSTRACT Although 60 million people are exposed to human African trypanosomiasis, drug companies have not been interested in developing new drugs due to the lack of financial reward. No new drugs will be available for several years. A clearer understanding of the distribution of existing drugs into the brains of sleeping sickness patients is needed if we are to use the treatments that are available more safely and effectively. This proposal addresses this issue by using established animal models. Using in situ brain perfusion and isolated incubated choroid plexus techniques, we investigated the distribution of [3H]suramin into the central nervous systems (CNSs) of male BALB/c, FVB (wild-type), and P-glycoprotein-deficient (Mdr1a/Mdr1b-targeted mutation) mice. There was no difference in the [3H]suramin distributions between the three strains of mice. [3H]suramin had a distribution similar to that of the vascular marker, [14C]sucrose, into the regions of the brain parenchyma that have a blood-brain barrier. However, the association of [3H]suramin with the circumventricular organ samples, including the choroid plexus, was higher than that of [14C]sucrose. The association of [3H]suramin with the choroid plexus was also sensitive to phenylarsine oxide, an inhibitor of endocytosis. The distribution of [3H]suramin to the brain was not affected by the presence of other antitrypanosomal drugs or the P-glycoprotein efflux transporter. Overall, the results confirm that [3H]suramin would be unlikely to treat the second or CNS stage of sleeping sickness.

Opiate-induced Analgesia Is Increased and Prolonged in Mice Lacking P-glycoprotein

2000 ◽  
Vol 92 (5) ◽  
pp. 1392-1399 ◽  
Author(s):  
Susan J. Thompson ◽  
Kari Koszdin ◽  
Christopher M. Bernards
Keyword(s):  
Knockout Mice ◽  
Transmembrane Protein ◽  
Analgesic Efficacy ◽  
Cell Types ◽  
Acute Administration ◽  
Morphine Analgesia ◽  
Wild Type ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors ◽  
The Brain

Background P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids. Methods Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined. Results Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice. Conclusions These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.

scholarly journals Diurnal Variation in P-glycoprotein-Mediated Transport and Cerebrospinal Fluid Turnover in the Brain

2014 ◽  
Vol 16 (5) ◽  
pp. 1029-1037 ◽  
Author(s):  
Laura Kervezee ◽  
Robin Hartman ◽  
Dirk-Jan van den Berg ◽  
Shinji Shimizu ◽  
Yumi Emoto-Yamamoto ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Diurnal Variation ◽  
P Glycoprotein ◽  
The Brain

Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice

1997 ◽  
Vol 272 (3) ◽  
pp. E485-E493 ◽  
Author(s):  
J. A. Palha ◽  
M. T. Hays ◽  
G. Morreale de Escobar ◽  
V. Episkopou ◽  
M. E. Gottesman ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Null Mouse ◽  
Tissue Uptake ◽  
Wild Type ◽  
Transfer Rates ◽  
Physiological Conditions ◽  
Liver And Kidney ◽  
The Brain ◽  
Brain Barriers

As part of a study on tissue uptake of thyroxine (T4) in a transthyretin (TTR)-null mouse strain, kinetic parameters of thyroxine metabolism in wild-type mice under normal physiological conditions are presented. Kinetic analysis of injected [(125)I]T4 showed that TTR-null mutants have markedly increased [(125)I]T4 transfer rate constants from plasma to the fast-exchange compartments of liver and kidney and from fast to slow kidney compartments. Transfer rates from plasma to brain, testes, and fat were little affected. The T4 tissue content in the mutants was greatly reduced in brain but relatively normal in liver and kidney. No major changes were observed in brain 3,3',5-triiodothyronine concentrations, suggesting that availability of this hormone is not markedly altered in the mutant mice. The low T4 brain content probably reflects the absence of T4-TTR complexes in the mutant choroid plexus and cerebrospinal fluid. This study indicates that TTR is not essential for T4 tissue uptake or for T4 to reach the brain across the choroid plexus-cerebrospinal fluid and/or blood-brain barriers.

scholarly journals The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid

2019 ◽  
Vol 38 (3) ◽  
pp. 574-583 ◽  
Author(s):  
Agnieszka Karbownik ◽  
Katarzyna Sobańska ◽  
Włodzimierz Płotek ◽  
Tomasz Grabowski ◽  
Agnieszka Klupczynska ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
P Glycoprotein ◽  
The Brain
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