Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier.

Abstract Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.

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Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

International Journal of Molecular Sciences ◽

10.3390/ijms221810045 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10045

Author(s):

Phuong Thao Do ◽

Chung-Che Wu ◽

Yung-Hsiao Chiang ◽

Chaur-Jong Hu ◽

Kai-Yun Chen

Keyword(s):

Stem Cells ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Time Window ◽

Brain Regions ◽

Brain Barrier ◽

Therapeutic Effects ◽

Pathophysiological Mechanism ◽

Cell Based Therapy ◽

Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1915778116 ◽

2019 ◽

Vol 116 (49) ◽

pp. 24796-24807 ◽

Cited By ~ 7

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.

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Blood-brain barrier permeability to sucrose and dextran after osmotic opening

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.247.4.r634 ◽

1984 ◽

Vol 247 (4) ◽

pp. R634-R638 ◽

Cited By ~ 4

Author(s):

Y. Z. Ziylan ◽

P. J. Robinson ◽

S. I. Rapoport

Keyword(s):

Blood Brain Barrier ◽

Brain Regions ◽

Brain Barrier ◽

Differential Rate ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Size Dependent ◽

Blood Brain ◽

Permeability Surface ◽

Brain Barrier Permeability

Regional cerebrovascular permeability-surface area (PA) products were calculated for two nonelectrolyte tracers differing considerably in molecular weight and size [( 14C]sucrose: mol wt 340 daltons, radius 5 A; and [3H]dextran: mol wt approximately 79,000 daltons, radius approximately 65 A) in control (uninfused) rats and in rats 6, 35, and 55 min after the blood-brain barrier was opened by a 30-s infusion of 1.8 molal L(+)-arabinose into a carotid artery. In control brain regions, mean PA for [14C]sucrose was 10(-5) s-1, whereas PA was not measurable for [3H]dextran. Six minutes after arabinose infusion, PA for both substances increased dramatically to 10(-4) s-1 or more; PA then declined at 35 and 55 min after arabinose infusion, but more markedly for [3H]dextran than for [14C]sucrose. The results demonstrate a size-dependent, differential rate of closure of the blood-brain barrier after osmotic opening. This is shown to be consistent with a pore model with bulk flow for blood-brain barrier permeability after osmotic opening.

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Influence of age on the passage of paraquat through the blood-brain barrier in rats: A distribution and pathological examination

Human & Experimental Toxicology ◽

10.1177/096032719601500308 ◽

1996 ◽

Vol 15 (3) ◽

pp. 231-236 ◽

Cited By ~ 36

Author(s):

PS Widdowson ◽

MJ Farnworth ◽

MG Simpson ◽

EA Lock

Keyword(s):

Blood Brain Barrier ◽

Neuronal Damage ◽

Lethal Dose ◽

Age Groups ◽

Brain Regions ◽

Adult Brain ◽

Brain Barrier ◽

Pathological Examination ◽

Neonatal Brain ◽

Blood Brain

Experiments were performed to determine the extent of paraquat entry into the brain of neonatal and elderly rats, as compared with adult rats, which may be dependent on the efficacy of the blood-brain barrier. A single, median lethal dose (20 mg/kg s.c.) of paraquat containing [14C]paraquat was administered to neonatal (10 day old), adult (3 month old) and elderly (18 month old) rats. In contrast to the adult and elderly rats where paraquat levels fell over the 24 h post-dosing period to negligible levels, paraquat concentrations in neonatal brains did not decrease with time between 0.5 and 24 h following dosing. The distribution of [14C]paraquat was measured in selective brain regions using quantitative autoradiogra phy in all three age groups of rats, 30 min and 24 h following dosing. Autoradiography demonstrated that brain paraquat distributions were similar in the rat age groups. Most of the paraquat was confined to regions outside the blood-brain barrier and to brain regions that lack a complete blood-brain barrier e.g. dorsal hypotha lamus, area postrema and the anterior olfactory bulb. Between 0.5 h and 24 h following dosing, paraquat concentrations in deeper brain structures, some distance away from the sites of entry, began to slowly increase in all the rat age groups. By 24 h following dosing, a majority of brain regions examined using quantitative autoradiogra phy revealed significantly higher paraquat concentrations in neonatal brains as compared to brain regions of adult and elderly rats. Despite increased paraquat entry into neonatal brain, we could find no evidence for paraquat- induced neuronal cell damage following a detailed histopathological examination of perfused-fixed brains. In conclusion, impaired blood-brain barrier integrity in neonatal brain thus permitting more paraquat to enter than in adult brain, did not result in neuronal damage.

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

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100031279 ◽

1991 ◽

Vol 18 (1) ◽

pp. 39-44 ◽

Cited By ~ 54

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.

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Vascular and perivascular cell profiling reveals the molecular and cellular bases of blood-brain barrier heterogeneity

10.1101/2021.04.26.441465 ◽

2021 ◽

Author(s):

Sarah J. Pfau ◽

Urs H. Langen ◽

Theodore M. Fisher ◽

Indumathi Prakash ◽

Faheem Nagpurwala ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Regions ◽

Brain Barrier ◽

Imaging Method ◽

Perivascular Cells ◽

Perivascular Cell ◽

Regional Specialization ◽

Neuronal Homeostasis ◽

Blood Brain ◽

The Central Nervous System

SUMMARYThe blood-brain barrier (BBB) is critical for protecting the brain and maintaining neuronal homeostasis. Although the BBB is a unique feature of the central nervous system (CNS) vasculature, not all brain regions have the same degree of impermeability. Differences in BBB permeability are important for controlling the local extracellular environment of specific brain regions to regulate the function and plasticity of particular neural circuits. However, how BBB heterogeneity occurs is poorly understood. Here, we demonstrate how regional specialization of the BBB is achieved. With unbiased cell profiling in small, defined brain regions, we compare the median eminence, which has a naturally leaky BBB, with the cortex, which has an impermeable BBB. We identify hundreds of molecular differences in endothelial cells (ECs) and demonstrate the existence of differences in perivascular astrocytes and pericytes in these regions, finding 3 previously unknown subtypes of astrocytes and several key differences in pericytes. By serial electron microscopy reconstruction and a novel, aqueous-based tissue clearing imaging method, we further reveal previously unknown anatomical specializations of these perivascular cells and their unique physical interactions with neighboring ECs. Finally, we identify ligand-receptor pairs between ECs and perivascular cells that may regulate regional BBB integrity in ECs. Using a bioinformatic approach we identified 26 and 26 ligand-receptor pairs underlying EC-pericyte and EC-astrocyte interactions, respectively. Our results demonstrate that differences in ECs, together with region-specific physical and molecular interactions with local perivascular cells, contribute to BBB functional heterogeneity. These regional cell inventories serve as a platform for further investigation of the dynamic and heterogeneous nature of the BBB in other brain regions. Identification of local BBB specializations provides insight into the function of different brain regions and will permit the development of region-specific drug delivery in the CNS.

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

10.1101/2020.07.15.205229 ◽

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

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