scholarly journals Adrenergic-Induced Enhancement of Brain Barrier System Permeability to Small Nonelectrolytes: Choroid Plexus versus Cerebral Capillaries

1985 ◽  
Vol 5 (3) ◽  
pp. 401-412 ◽  
Author(s):  
Vincent A. Murphy ◽  
Conrad E. Johanson
Keyword(s):  
Choroid Plexus ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Brain Barrier ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Acute Hypertension ◽  
Adrenergic Agents ◽  
Cerebral Capillaries ◽  
Choroid Plexuses

Acute hypertension induced by adrenergic agents opens up the blood–CSF barrier (choroid plexus) to nonelectrolyte and protein tracers. Sprague-Dawley adult rats anesthetized with ketamine were given an intravenous bolus of either epinephrine (10 μg/kg), phenylephrine (100 μg/kg), isoproterenol (10 μg/kg), or d,l-amphetamine (2 mg/kg). Tracers were injected simultaneously with test agents, and the animals killed 10 min later. Epinephrine raised MABP by 57 mm Hg, to a peak pressure of 160 mm Hg; and it increased the volume of distribution ( Vd) of urea, mannitol, and 125I-bovine serum albumin in CSF by 1.5-, 2.7-, and 30-fold, respectively. There was enhanced uptake by lateral and fourth ventricle choroid plexuses, cerebral cortex, cerebellum, medulla, and thalamus. Phenylephrine also elevated MABP to 160 mm Hg, but it increased permeation of tracers into CSF (and several brain regions) to a lesser extent than epinephrine, attributable to protective vasoconstriction associated with α-agonist activity. Ratio analysis of Vd data provides evidence that augmented permeation of nonelectrolyte tracers in acute hypertension occurs predominantly by diffusion rather than vesicular transport. It is postulated that elevated MABP distends the central cores of choroid plexus villi and cerebral capillaries, with resultant stretching and opening of tight junctions in both barrier systems; with less hindrance to diffusion, urea and mannitol are cleared at rates closer to free diffusion. Neither isoproterenol (decreased MABP by 40 mm Hg) nor amphetamine (did not alter MABP) significantly opened the choroid plexus or blood–brain barrier to tracers.

Permeability of blood-brain barrier to various sized molecules

1985 ◽  
Vol 248 (5) ◽  
pp. H712-H718 ◽  
Author(s):  
W. G. Mayhan ◽  
D. D. Heistad
Keyword(s):  
Blood Brain Barrier ◽  
Fluorescent Microscopy ◽  
Brain Barrier ◽  
Sprague Dawley ◽  
Acute Hypertension ◽  
Size Dependent ◽  
Blood Brain ◽  
Sprague Dawley Rats ◽  
Intravital Fluorescent Microscopy ◽  
Dextran Clearance

We studied disruption of the blood-brain barrier (BBB) by acute hypertension and a hyperosmolar solution. The goals were to determine whether 1) disruption of the BBB occurs primarily in arteries, capillaries, or veins, and 2) transport of different-sized molecules is homogeneous or size dependent. Sprague-Dawley rats were studied using intravital fluorescent microscopy of pial vessels and fluorescein-labeled dextrans (FITC-dextran, mol wt = 70,000, 20,000, and 4,000 daltons). The site of disruption was determined by the appearance of microvascular leaky sites. Transport of different-sized molecules was calculated from clearance of FITC-dextran. During gradual hypertension and osmotic disruption, all leaky sites were venular. Rapid hypertension produced venular leaky sites and, in some experiments, diffuse arteriolar extravasation of FITC-dextran. Clearance of different-sized molecules was homogeneous during acute hypertension. In contrast, clearance of molecules during osmotic disruption was size dependent. The findings suggest that 1) venules and veins are the primary sites of disruption following acute hypertension and a hyperosmolar solution; 2) transport of different-sized molecules is homogeneous following acute hypertension, which suggests a vesicular mechanism; and 3) transport following hyperosmolar disruption is size dependent, which suggests that hyperosmolar disruption may involve formation of pores as well as vesicular transport.

scholarly journals Transfer Constants for Blood-Brain Barrier Permeation of the Neuroexcitatory Shellfish Toxin, Domoic Acid

1991 ◽  
Vol 18 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Edward Preston ◽  
Ivo Hynie
Keyword(s):  
Blood Brain Barrier ◽  
Domoic Acid ◽  
Carrier Transport ◽  
Polar Compounds ◽  
Brain Regions ◽  
Brain Barrier ◽  
Adult Rats ◽  
Mean Values ◽  
Blood Brain ◽  
The Brain

ABSTRACT:The cause of the toxic mussel poisoning episode in 1987 was traced to a plankton-produced excitotoxin, domoic acid. Experiments were undertaken to quantitate the degree to which blood-borne domoic acid can permeate the microvasculature to enter the brain. Pentobarbital-anesthetized, adult rats received an i.v. injection of 3H-domoic acid which was permitted to circulate for 3-60 min. Transfer constants (Ki) describing blood-to-brain diffusion of tracer were calculated from analysis of the relationship between brain vs plasma radioactivity with time. Mean values (mL.g-1.s-1 x 106) for permeation into 7 brain regions (n = 10 rats) ranged from 1.60 ± 0.13 (SE) to 1.86 ± 0.33 (cortex, ponsmedulla respectively), and carrier transport or regional selectivity in uptake were not evident. Nephrectomy prior to domoic acid injection resulted in the elevation of circulating plasma tracer level and brain uptake. The Ki values are comparable to those for other polar compounds such as sucrose, and indicate that the blood-brain barrier greatly limits the amount of toxin that enters the brain. Together with absorbed dosage, integrity of the cerebrovascular barrier and normal kidney function are important to the outcome of accidentally ingesting domoic acid.

Regional blood-brain barrier transport of cationized bovine serum albumin in awake rats

1991 ◽  
Vol 261 (2) ◽  
pp. R478-R483
Author(s):  
M. Shimon-Hophy ◽  
K. C. Wadhwani ◽  
K. Chandrasekaran ◽  
D. Larson ◽  
Q. R. Smith ◽  
...  
Keyword(s):  
Bovine Serum Albumin ◽  
Serum Albumin ◽  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Bovine Serum ◽  
Brain Slices ◽  
Brain Regions ◽  
Brain Barrier ◽  
Sprague Dawley ◽  
Blood Brain

Regional blood-brain barrier permeability-surface area products (PAs) of cationized bovine serum albumin (cBSA) with isoelectric point (pI) approximately 8 or greater than or equal to 11 and of native bovine serum albumin (nBSA;pI approximately 4) were determined in awake male Sprague-Dawley rats after bolus intravenous injection. The albumins were labeled with 125I. Brain uptakes were assessed by autoradiography and by direct assay of radioactivity in brain regions. nBSA uptake into brain was statistically insignificant over 3 h, whereas cBSA uptake was significantly even at 6 min. Mean PA values of cBSA with pI approximately 11 (1.69-2.65 x 10(-5) ml.s-1.g-1) in most brain regions were twofold higher than PAs of cBSA with pI approximately 8 (0.98-1.37 x 10(-5) ml.s-1.g-1), whereas mean PA for nBSA did not differ significantly from zero. Autoradiographs of brain slices and net distributions in brain compartments at 6 and 30 min after injection suggested that cBSA entered the brain parenchyma via blood vessels and cerebrospinal fluid but that the former was the main route. The results quantitate for the first time regional brain PA values for cationized proteins and suggest specific mechanisms at cerebral blood vessels that distinguish transport of cationized from noncationized macromolecules.

scholarly journals Examination of the Blood-to-Brain Transfer of α-Aminoisobutyric Acid and Horseradish Peroxidase: Regional Alterations in Blood—Brain Barrier Function following Acute Hypertension

1986 ◽  
Vol 6 (4) ◽  
pp. 471-480 ◽  
Author(s):  
Mary D. Ellison ◽  
John T. Povlishock ◽  
Ronald L. Hayes
Keyword(s):  
Horseradish Peroxidase ◽  
Blood Brain Barrier ◽  
Brain Regions ◽  
Brain Barrier ◽  
Acute Hypertension ◽  
Aminoisobutyric Acid ◽  
Protein Extravasation ◽  
Blood Brain ◽  
Infusion Of Norepinephrine ◽  
The Brain

Blood–brain barrier (BBB) alterations following acute hypertension were studied in rats, employing as tracers in each animal both horseradish peroxidase (HRP) (MW 40,000) and [14C]α-aminoisobutyric acid ([14C]AIB) (MW 104). Eighteen animals were subjected to acute hypertension induced by the intravenous infusion of norepinephrine bitartrate (NE) (Levophed). Five animals injected with both tracers but not infused with NE served as controls. The brain of each animal was serially sectioned with adjacent sections processed either for macroautoradiography or for light microscopic visualization of HRP reaction product via histochemical reaction with tetramethylbenzidine. Quantitative blood-to-brain transfer constants for AIB were determined in each of 14 brain regions. Qualitative comparisons were also made between the AIB and HRP blood-to-brain extravasation patterns in each group. Acute hypertension increased cerebrovascular permeability to both AIB and HRP in most animals. Topographically, the sites of the most highly elevated AIB transfer corresponded with sites of HRP extravasation. Conversely, all sites of protein passage corresponded spatially to sites of elevated AIB transfer. Brain regions commonly showing increased permeability to both tracers included the cerebral cortices, corpus callosum, and thalamus. Importantly, some brain regions showed elevated AIB transfer constants where protein extravasation was absent. These regions included the caudate–putamen, hippocampus, basal forebrain, and cerebellum. These observations suggest that following acute hypertension, alterations in BBB permeability are not limited to vascular segments allowing protein extravasation.

Further evidence that the blood/brain barrier impedes paraquat entry into the brain

1995 ◽  
Vol 14 (7) ◽  
pp. 587-594 ◽  
Author(s):  
JL Naylor ◽  
PS Widdowson ◽  
MG Simpson ◽  
M. Farnworth ◽  
MK Ellis ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Area Postrema ◽  
Neuronal Cell ◽  
Brain Regions ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Adult Rats ◽  
Male Adult ◽  
Blood Brain ◽  
The Brain

The distribution of the non-selective herbicide paraquat was examined in the brain following subcutaneous admin istration of 20 mg kg -1 paraquat ion containing [14C]paraquat to male adult rats in order to determine whether paraquat crosses the blood/brain barrier. Following administration, [14C]paraquat reached a maxi mal concentration in the brain (0.05% of administered dose) within the first hour and then rapidly disappeared from the brain. However, 24 h after administration of the herbicide, about 13% of the maximal recorded concentra tion of paraquat remained in the brain (1.6 nmol g-1 wet weight) and could not be removed by intracardiac perfu sion. Using measurements of [14C]paraquat in dissected brain regions and using quantitative autoradiography we demonstrated an asymmetrical distribution in and around the brain at 30 min (maximal concentration) and 24 h after administration. Most of the paraquat was associated with five structures, two of which, the pineal gland and linings of the cerebral ventricles lie outside the blood/brain barrier whilst the remaining three brain areas, the anterior portion of the olfactory bulb, hypothalamus and area postrema do not have a blood/brain barrier. Overall, the distribution of [14C]paraquat in the brain 24 h after systemic administration was highly correlated to the blood volume. These data indicate that any remaining paraquat in the brain 24 h after systemic administration is associated with elements of the cerebro-circulatory sys tem, such as the endothelial cells that make up the capil lary network and that there is a limited entry of paraquat into brain regions without a blood/brain barrier. No [14C]paraquat was detected in regions where there has been demonstrated pathology in brains from humans with Parkinson's disease. Finally, we could find no evidence for paraquat-induced neuronal cell necrosis 24 or 48 h after systemic administration. Overall it may be concluded that systemically administered paraquat does not pose a direct major neurotoxicological risk in the majority of brain regions which have a functional blood/brain barrier since paraquat can be excluded from the brain by this barrier.

Disruption of blood-brain barrier during acute hypertension in adult and aged rats

1990 ◽  
Vol 258 (6) ◽  
pp. H1735-H1738 ◽  
Author(s):  
W. G. Mayhan
Keyword(s):  
Arterial Pressure ◽  
Blood Brain Barrier ◽  
Wistar Rats ◽  
Fluorescent Microscopy ◽  
Systemic Arterial Pressure ◽  
Brain Barrier ◽  
Aged Rats ◽  
Adult Rats ◽  
Acute Hypertension ◽  
Blood Brain

The goal of this study was to determine whether the susceptibility of the blood-brain barrier to disruption during acute hypertension is altered in aged rats. Intravital fluorescent microscopy and fluorescein-labeled albumin were used to evaluate disruption of the blood-brain barrier during acute hypertension in adult Wistar rats (6-8 mo) and aged Wistar rats (24-26 mo). Permeability of the blood-brain barrier albumin and by counting the number of microvascular leaky sites under control conditions and during acute arterial hypertension in adult and aged rats. Pressure in pial venules, which are the primary site of disruption of the blood-brain barrier during acute hypertension, and in pial arterioles was measured using a servo-null device. In adult rats, when systemic arterial pressure was increased from 124 +/- 5 (means +/- SE) to 190 +/- 5 mmHg, clearance of albumin increased from 0.10 +/- 0.05 to 1.64 +/- 0.76 X 10(-6) ml/s. In aged rats, when systemic arterial pressure was increased from 116 +/- 4 to 185 +/- 3 mmHg, clearance of albumin increased from 0.10 +/- 0.03 to 1.56 +/- 0.49 X 10(-6) ml/s. Increases in pial venular pressure and pial arteriolar pressure also were similar in adult and aged rats. Thus the findings suggest that the susceptibility of the blood-brain barrier to disruption during acute hypertension is similar in adult and aged rats.

Permeability of the microcirculation in area postrema of rat

1988 ◽  
Vol 46 ◽  
pp. 348-349
Author(s):  
Shams M. Ghoneim ◽  
Frank M. Faraci ◽  
Gary L. Baumbach
Keyword(s):  
Brain Stem ◽  
Area Postrema ◽  
Upper Body ◽  
Sprague Dawley ◽  
Sodium Cacodylate ◽  
Acute Hypertension ◽  
Sprague Dawley Rats ◽  
Ultrastructural Characteristics ◽  
The Brain ◽  
Adjacent Brain

The area postrema is a circumventricular organ in the brain stem and is one of the regions in the brain that lacks a fully functional blood-brain barrier. Recently, we found that disruption of the microcirculation during acute hypertension is greater in area postrema than in the adjacent brain stem. In contrast, hyperosmolar disruption of the microcirculation is greater in brain stem. The objective of this study was to compare ultrastructural characteristics of the microcirculation in area postrema and adjacent brain stem.We studied 5 Sprague-Dawley rats. Horseradish peroxidase was injected intravenously and allowed to circulate for 1, 5 or 15 minutes. Following perfusion of the upper body with 2.25% glutaraldehyde in 0.1 M sodium cacodylate, the brain stem was removed, embedded in agar, and chopped into 50-70 μm sections with a TC-Sorvall tissue chopper. Sections of brain stem were incubated for 1 hour in a solution of 3,3' diaminobenzidine tetrahydrochloride (0.05%) in 0.05M Tris buffer with 1% H2O2.

Brain Aromatase in Control Versus Castrated Norway Brown, Sprague-Dawley and Wistar Adult Rats

1999 ◽  
Vol 221 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Lori J. Mathias ◽  
Nathan A. Jacobson ◽  
Reuben W. Rhees ◽  
Edwin D. Lephart
Keyword(s):  
Sprague Dawley ◽  
Adult Rats ◽  
Brain Aromatase ◽  
Control Versus

scholarly journals The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sébastien Goutal ◽  
Martine Guillermier ◽  
Guillaume Becker ◽  
Mylène Gaudin ◽  
Yann Bramoullé ◽  
...  
Keyword(s):  
Slow Component ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Pharmacokinetic Data ◽  
Limited Information ◽  
Positron Emission ◽  
Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

scholarly journals Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague–Dawley rats exposed to glutathione deficit during early postnatal development of the brain

2021 ◽  
Author(s):  
Marta A. Lech ◽  
Kinga Kamińska ◽  
Monika Leśkiewicz ◽  
Elżbieta Lorenc-Koci ◽  
Zofia Rogóż
Keyword(s):  
Mrna Expression ◽  
Postnatal Development ◽  
Repeated Treatment ◽  
Sprague Dawley ◽  
Biochemical Tests ◽  
Bdnf Mrna ◽  
Adult Rats ◽  
Behavioral Deficits ◽  
Glutathione Synthesis ◽  
Early Postnatal Development

Abstract Background Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. Methods In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5–p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90–92 rats were evaluated in the behavioral and biochemical tests. Results BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. Conclusion The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

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