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 Distribution of Glycylsarcosine and Cefadroxil among Cerebrospinal Fluid, Choroid Plexus, and Brain Parenchyma after Intracerebroventricular Injection is Markedly Different between Wild-Type and Pept2 Null Mice

2010 ◽  
Vol 31 (1) ◽  
pp. 250-261 ◽  
Author(s):  
David E Smith ◽  
Yongjun Hu ◽  
Hong Shen ◽  
Tavarekere N Nagaraja ◽  
Joseph D Fenstermacher ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Interstitial Fluid ◽  
Brain Parenchyma ◽  
Wild Type ◽  
Septal Region ◽  
Biodistribution Studies ◽  
Choroid Plexuses ◽  
Clearance Kinetics ◽  
The Brain

The purpose of this study was to define the cerebrospinal fluid (CSF) clearance kinetics, choroid plexus uptake, and parenchymal penetration of PEPT2 substrates in different regions of the brain after intracerebroventricular administration. To accomplish these objectives, we performed biodistribution studies using [14C]glycylsarcosine (GlySar) and [3H]cefadroxil, along with quantitative autoradiography of [14C]GlySar, in wild-type and Pept2 null mice. We found that PEPT2 deletion markedly reduced the uptake of GlySar and cefadroxil in choroid plexuses at 60 mins by 94% and 82% ( P<0.001), respectively, and lowered their CSF clearances by about fourfold. Autoradiography showed that GlySar concentrations in the lateral, third, and fourth ventricle choroid plexuses were higher in wild-type as compared with Pept2 null mice ( P<0.01). Uptake of GlySar by the ependymal–subependymal layer and septal region was higher in wild-type than in null mice, but the half-distance of penetration into parenchyma was significantly less in wild-type mice. The latter is probably because of the clearance of GlySar from interstitial fluid by brain cells expressing PEPT2, which stops further penetration. These studies show that PEPT2 knockout can significantly modify the spatial distribution of GlySar and cefadroxil (and presumably other peptides/mimetics and peptide-like drugs) in brain.

scholarly journals Transfer of rhodamine-123 into the brain and cerebrospinal fluid of fetal, neonatal and adult rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Liam M. Koehn ◽  
Katarzyna M. Dziegielewska ◽  
Mark D. Habgood ◽  
Yifan Huang ◽  
Norman R. Saunders
Keyword(s):  
Cerebrospinal Fluid ◽  
Fetal Brain ◽  
Maternal Blood ◽  
Adult Brain ◽  
Rhodamine 123 ◽  
Patient Specific ◽  
Adult Rats ◽  
Blood Brain ◽  
The Brain ◽  
Brain Barriers

Abstract Background Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. Methods In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (concentration ratios between tissue and plasma ratios) were determined using Kruskal-Wallis tests with Dunn’s corrections. Results Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20 %. Of the R123 that reached fetal circulation 43 % transferred into brain and 38 % into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43 % at P4, 22 % at P14 and 9 % in adults; CSF: 8 % at P4, 8 % at P14 and 1 % in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 9 %, similar to the transfer across adult blood-brain barriers (also 9 %). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p < 0.05). Conclusions Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis.

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.

scholarly journals High Blood Pressure Effects on the Blood to Cerebrospinal Fluid Barrier and Cerebrospinal Fluid Protein Composition: A Two-Dimensional Electrophoresis Study in Spontaneously Hypertensive Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Ibrahim González-Marrero ◽  
Leandro Castañeyra-Ruiz ◽  
Juan M. González-Toledo ◽  
Agustín Castañeyra-Ruiz ◽  
Hector de Paz-Carmona ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Protein Composition ◽  
Pressure Effects ◽  
Apolipoprotein A1 ◽  
Spontaneously Hypertensive ◽  
Barrier Disruption ◽  
Cerebrospinal Fluid Proteins ◽  
The Brain ◽  
Cerebrospinal Fluid Protein

The aim of the present work is to analyze the cerebrospinal fluid proteomic profile, trying to find possible biomarkers of the effects of hypertension of the blood to CSF barrier disruption in the brain and their participation in the cholesterol andβ-amyloid metabolism and inflammatory processes. Cerebrospinal fluid (CSF) is a system linked to the brain and its composition can be altered not only by encephalic disorder, but also by systemic diseases such as arterial hypertension, which produces alterations in the choroid plexus and cerebrospinal fluid protein composition. 2D gel electrophoresis in cerebrospinal fluid extracted from the cistern magna before sacrifice of hypertensive and control rats was performed. The results showed different proteomic profiles between SHR and WKY, thatα-1-antitrypsin, apolipoprotein A1, albumin, immunoglobulin G, vitamin D binding protein, haptoglobin andα-1-macroglobulin were found to be up-regulated in SHR, and apolipoprotein E, transthyretin,α-2-HS-glycoprotein, transferrin,α-1β-glycoprotein, kininogen and carbonic anhidrase II were down-regulated in SHR. The conclusion made here is that hypertension in SHR produces important variations in cerebrospinal fluid proteins that could be due to a choroid plexus dysfunction and this fact supports the close connection between hypertension and blood to cerebrospinal fluid barrier disruption.

scholarly journals 280.Reproductive consequences of circadian dysfunction: fertility in the Bmal1 null mouse

2004 ◽  
Vol 16 (9) ◽  
pp. 280 ◽  
Author(s):  
M. J. Boden ◽  
D. J. Kennaway
Keyword(s):  
Clock Genes ◽  
Reproductive Function ◽  
Blastocyst Stage ◽  
Null Mouse ◽  
Wild Type ◽  
Peripheral Tissues ◽  
Seminal Vesicle Weight ◽  
Natural Mating ◽  
Reproductive Consequences ◽  
The Brain

Circadian rhythms are generated by a suite of genes called clock genes that are expressed in the brain and also in many peripheral tissues. In the peripheral tissues, these genes assist in regulating the expression of many genes involved in cell growth, angiogenesis and development. Bmal1 is a critical gene involved in circadian rhythm generation. Here we report on the fertility and fecundity of Bmal1 knockout mice (Bmal1–/–). Male Bmal1–/– mice have impaired fertility compared to controls [(litters produced/number of animals) wild type (5/5), CBA controls (5/5), Bmal1–/– (1/15)]. Fifty percent of male Bmal1–/– mice had defective caudal sperm, showing sperm that was both non-motile and malformed. Seminal vesicle weight was significantly reduced in the Bmal1–/– mice (50% reduction) in males at both 4 and 5.5 months old. Female Bmal1–/– mice had irregular oestrus cycles and failed to maintain a pregnancy to term following natural mating [(litters produced/number of animals) wild type (5/5) CBA controls (5/5) Bmal1–/– (0/5)]. When embryos were flushed from the uterus 4 days after natural mating, there was a reduced number of released oocytes and a reduced development to blastocysts in the Bmal1–/– female mice. Following a standard PMSG/HCG super ovulation protocol, Bmal1–/– mice showed both a reduction in ovulation rate as well as a slowed progression of embryos to blastocyst stage (Table 1, see PDF file). These results suggest that disruption of a key clock gene has detrimental consequences on fertility in the mouse. Further, this reduction in fertility appears to be acting at multiple levels. Continued investigation into the importance of rhythm genes in reproductive function is required.

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.

Intracranial Pressure

2019 ◽  
pp. 69-73
Author(s):  
Eelco F. M. Wijdicks ◽  
William D. Freeman
Keyword(s):  
Cerebrospinal Fluid ◽  
Smooth Muscle ◽  
Choroid Plexus ◽  
Blood Cells ◽  
White Blood Cells ◽  
Ependymal Cells ◽  
Cerebral Aqueduct ◽  
Epithelial Surface ◽  
The Brain ◽  
Route Of Delivery

Cerebrospinal fluid (CSF) fills the subarachnoid space, spinal canal, and ventricles of the brain. CSF is enclosed within the brain by the pial layer, ependymal cells lining the ventricles, and the epithelial surface of the choroid plexus, where it is largely produced. Choroid plexus is present throughout the ventricular system with the exception of the frontal and occipital horns of the lateral ventricle and the cerebral aqueduct. The vascular smooth muscle and the epithelium of the choroid plexus receive both sympathetic and parasympathetic input. In an adult, CSF is normally acellular. A normal spinal sample may contain up to 5 white blood cells (WBCs) or red blood cells (RBCs). CSF allows for a route of delivery and removal of nutrients, hormones, and transmitters for the brain.

scholarly journals Choroid plexus volume after stroke

2019 ◽  
Vol 14 (9) ◽  
pp. 923-930 ◽  
Author(s):  
Natalia Egorova ◽  
Elie Gottlieb ◽  
Mohamed Salah Khlif ◽  
Neil J Spratt ◽  
Amy Brodtmann
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Brain Aging ◽  
Automatic Segmentation ◽  
Accelerated Expansion ◽  
First Year ◽  
Intracranial Volume ◽  
Cross Sectional ◽  
Lateral Ventricles ◽  
The Brain

Background Cerebrospinal fluid circulation is crucial for the functioning of the brain. Aging and brain pathologies such as Alzheimer’s disease have been associated with a change in the morphology of the ventricles and the choroid plexus. Despite the evidence from animal models that the cerebrospinal fluid system plays an important role in neuroinflammation and the restoration of the brain after ischemic brain injury, little is known about changes to the choroid plexus after stroke in humans. Aims Our goal was to characterize structural choroid plexus changes poststroke. Methods We used an automatic segmentation tool to estimate the volumes of choroid plexus and lateral ventricles in stroke and control participants at three time points (at baseline, 3 and 12 months) over the first year after stroke. We assessed group differences cross-sectionally at each time point and longitudinally. For stroke participants, we specifically differentiated between ipsi- and contra-lesional volumes. Statistical analyses were conducted for each region separately and included covariates such as age, sex, total intracranial volume, and years of education. Results We observed significantly larger choroid plexus volumes in stroke participants compared to controls in both cross-sectional and longitudinal analyses. Choroid plexus volumes did not exhibit any change over the first year after stroke, with no difference between ipsi- and contra-lesional volumes. This was in contrast to the volume of lateral ventricles that we found to enlarge over time in all participants, with more accelerated expansion in stroke survivors ipsi-lesionally. Conclusions Our results suggest that chronic stages of stroke are characterized by larger choroid plexus volumes, but the enlargement likely takes place prior to or very early after the stroke incident.

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.

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