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.

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.

scholarly journals Nose-to-Brain Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 138 ◽  
Author(s):  
Paolo Giunchedi ◽  
Elisabetta Gavini ◽  
Maria Cristina Bonferoni
Keyword(s):  
Side Effects ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Brain Delivery ◽  
Special Issue ◽  
Drug Bioavailability ◽  
Blood Brain ◽  
The Brain

Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”.

scholarly journals Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection

2019 ◽  
Vol 116 (49) ◽  
pp. 24796-24807 ◽  
Author(s):  
Christine A. Schneider ◽  
Dario X. Figueroa Velez ◽  
Ricardo Azevedo ◽  
Evelyn M. Hoover ◽  
Cuong J. Tran ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Light Sheet ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cell Segmentation ◽  
Cns Infection ◽  
Light Sheet Microscopy ◽  
Blood Brain ◽  
The Brain

Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.

scholarly journals The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation

2020 ◽  
Author(s):  
Elizabeth M. Rhea ◽  
Aric F. Logsdon ◽  
Kim M. Hansen ◽  
Lindsey Williams ◽  
May Reed ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Blood Brain Barrier ◽  
Apoe Genotype ◽  
Brain Regions ◽  
Brain Barrier ◽  
Productive Infection ◽  
Peripheral Tissues ◽  
Blood Brain ◽  
Commercial Sources ◽  
The Brain

AbstractEvidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 ± 0.024 μL/g-min and 0.294 ± 0.032 μL/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10th the amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis.Graphical Abstract

scholarly journals Sustained Microglial Activation in the Area Postrema of Collagen-induced Arthritis Mice: a Potential Pathway Linking Arthritis and the Brain

2021 ◽  
Author(s):  
Takayuki Matsushita ◽  
Kazuhiro Otani ◽  
Yohsuke Oto ◽  
Yukari Takahashi ◽  
Daitaro Kurosaka ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Calcium Binding ◽  
Area Postrema ◽  
Chronic Phase ◽  
Principal Component ◽  
Brain Barrier ◽  
Collagen Induced Arthritis ◽  
Blood Brain ◽  
Blood Cytokines ◽  
The Brain

Abstract Background. Neuropsychological symptoms are common complications among patients with rheumatoid arthritis (RA), while it is largely unexplored how RA pathology spread to brain protected by blood-brain barrier (BBB). The sensory circumventricular organs (sCVOs) (brain regions lacking a blood–brain barrier) is the brain site that peripheral inflammatory signals, such as blood cytokines and chemokines, can directly access and modulate cell activities in the brain parenchyma. To determine whether microglia, resident immune cells in neuronal tissue, in the sCVOs can function as an interface between peripheral inflammation and brain under the autoimmune-arthritis conditions, we analyzed microglia in the sCVOs of a mouse model of collagen-induced arthritis (CIA).Methods. Microglial number and morphology were analyzed in the sCVOs of CIA and control mice (controls were administrated Freund’s adjuvant [FA] and/or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: “pre-onset” (post-immunization day [PID] 21), ”establishment” (PID 35), and “chronic” (PID 56 and 84). Quantitative analyses on microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression in microglia was also analyzed by multiple fluorescent in situ hybridization.Results. In the area postrema (AP), one of the sCVOs located in the medulla, microglia significantly increased in density (CIA, n = 15; FA, n = 6; saline: n = 10) with changes in morphology during the establishment and chronic phases. In other sCVOs (subfornical organs [SFO] and organum vasculosum laminae terminalis [OVLT]), microglial changes were not significant. In the AP microglia, non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of microglia in a highly activated form was increased in the CIA group. Also, the density of IL-1β-positive microglia, a hallmark of functional activation, increased in the AP. These microglial changes in the AP persisted until the chronic phase.Conclusions. Our findings indicate that an increase and activation of microglia is sustained in the AP during chronic arthritis. This suggests that there is a direct physiological pathway linking peripheral arthritis to the brain through the AP.

scholarly journals Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration

Biomaterials ◽  
2018 ◽  
Vol 176 ◽  
pp. 71-83 ◽  
Author(s):  
Xintao Zhang ◽  
Ting He ◽  
Zheng Chai ◽  
R. Jude Samulski ◽  
Chengwen Li
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Administration ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

scholarly journals Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 967
Author(s):  
Catarina Chaves ◽  
Tuan-Minh Do ◽  
Céline Cegarra ◽  
Valérie Roudières ◽  
Sandrine Tolou ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Structures ◽  
Brain Regions ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Slc Transporters ◽  
Blood Brain ◽  
The Brain ◽  
Human Primate

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were Investig.igated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.

scholarly journals Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 494
Author(s):  
Jin Kwon Jeong ◽  
Samantha A. Dow ◽  
Colin N. Young
Keyword(s):  
Blood Brain Barrier ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Area Postrema ◽  
Brain Regions ◽  
Circumventricular Organs ◽  
Brain Barrier ◽  
Neuroendocrine Control ◽  
Blood Brain ◽  
Cellular Machinery

The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals—pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recognized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.

Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults

1996 ◽  
Vol 271 (6) ◽  
pp. R1594-R1601 ◽  
Author(s):  
B. S. Stonestreet ◽  
C. S. Patlak ◽  
K. D. Pettigrew ◽  
C. B. Reilly ◽  
H. F. Cserr
Keyword(s):  
Blood Brain Barrier ◽  
Barrier Function ◽  
Brain Regions ◽  
Brain Barrier ◽  
Small Molecular Weight ◽  
Regional Heterogeneity ◽  
Regional Brain ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Brain

The ontogeny of regional blood-brain barrier function was quantified with the rate constant for influx (Ki) across the blood-brain barrier with the small molecular weight synthetic, inert hydrophilic amino acid alpha-aminoisobutyric acid (AIB) in chronically instrumented early (87 days of gestation, 60% of gestation) and late (137 days of gestation, 90% of gestation) gestation fetal, newborn (3 days of age), older (24 days of age), and adult (3 years of age) sheep. The Ki was significantly (P < 0.05) lower in the brain regions of the adult sheep and in most brain regions of newborn and older lambs compared with fetuses at 60 and 90% of gestation. The Ki exhibited regional brain heterogeneity (P < 0.05) in the five groups. The patterns of regional heterogeneity were accentuated (P < 0.05) in the younger groups. We conclude that ontogenic decreases in blood-brain barrier permeability are observed in ovine fetuses from 60% of gestation to maturity in the adult.

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.

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