scholarly journals Dorsal skull meningeal lymphatic vessels drain blood-solutes after intracerebral hemorrhage

2021 ◽  
Author(s):  
Anaïs Virenque ◽  
Raz Balin ◽  
Francesco M. Noe
Keyword(s):  
Cerebrospinal Fluid ◽  
Intracerebral Hemorrhage ◽  
Therapeutic Target ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Cerebrospinal Fluid Drainage ◽  
Preclinical Models ◽  
Local Formation ◽  
Two Photon

AbstractDrainage of intraparenchymal hematoma is crucial for the treatment of intracerebral hemorrhage (ICH). We investigated here the possible function of the meningeal lymphatic vessels (mLVs) in ICH resolution. Meningeal lymphatics have been reported to be involved in cerebrospinal fluid drainage, but their role in the drainage and clearance of brain parenchyma has not been characterized in details. Using two preclinical models of ICH, mimicking focal cortical ischemic hemorrhage and subcortical extended hemorrhage, we characterized the dynamics of blood drainage through the dorsal mLVs by two-photon real time imaging in awake mice. After ICH induction, we observe the flow of blood-derived components within the mLVs, suggesting that meningeal lymphatics can play a role in facilitating the drainage of the hemorrhage. We also found that local formation of new mLVs is directly correlated with ICH-related neuroinflammation levels. These findings suggest that meningeal lymphatics could provide a valuable therapeutic target for ICH resolution.SummaryIn vivo awake imaging reveals the direct drainage of extravasated blood-solutes from brain parenchyma into dorsal meningeal lymphatic vessels, following focal or diffuse intracranial hemorrhage

The perivascular pathways for influx of cerebrospinal fluid are most efficient in the midbrain

2017 ◽  
Vol 131 (22) ◽  
pp. 2745-2752 ◽  
Author(s):  
Howard Dobson ◽  
Matthew MacGregor Sharp ◽  
Richard Cumpsty ◽  
Theodore P. Criswell ◽  
Tyler Wellman ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Cerebrospinal Fluid ◽  
Subarachnoid Space ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Basement Membranes ◽  
Post Mortem ◽  
Cervical Lymph Nodes ◽  
The Brain

Although there are no conventional lymphatic vessels in the brain, fluid and solutes drain along basement membranes (BMs) of cerebral capillaries and arteries towards the subarachnoid space and cervical lymph nodes. Convective influx/glymphatic entry of the cerebrospinal fluid (CSF) into the brain parenchyma occurs along the pial-glial BMs of arteries. This project tested the hypotheses that pial-glial BM of arteries are thicker in the midbrain, allowing more glymphatic entry of CSF. The in vivo MRI and PET images were obtained from a 4.2-year-old dog, whereas the post-mortem electron microscopy was performed in a 12-year-old dog. We demonstrated a significant increase in the thickness of the pial-glial BM in the midbrain compared with the same BM in different regions of the brain and an increase in the convective influx of fluid from the subarachnoid space. These results are highly significant for the intrathecal drug delivery into the brain, indicating that the midbrain is better equipped for convective influx/glymphatic entry of the CSF.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

scholarly journals Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

2019 ◽  
Author(s):  
Felix C. Nebeling ◽  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Manuel Mittag ◽  
Julia Steffen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Brain Parenchyma ◽  
Two Photon ◽  
Contact Rates ◽  
Health And Disease ◽  
The Impact ◽  
The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

scholarly journals Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels

2019 ◽  
Vol 216 (11) ◽  
pp. 2492-2502 ◽  
Author(s):  
Qiaoli Ma ◽  
Yann Decker ◽  
Andreas Müller ◽  
Benjamin V. Ineichen ◽  
Steven T. Proulx
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Space ◽  
Near Infrared ◽  
Cranial Nerves ◽  
Lymphatic Vessels ◽  
Intraventricular Injection ◽  
Spinal Subarachnoid Space ◽  
Cord Injury ◽  
Sacral Spine

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.

In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology

2021 ◽  
pp. 1-14
Author(s):  
Christiana Bjorkli ◽  
Claire Louet ◽  
Trude Helen Flo ◽  
Mary Hemler ◽  
Axel Sandvig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Intracerebral Microdialysis ◽  
Preclinical Models ◽  
The Brain

Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 806-812 ◽  
Author(s):  
Eric Hatterer ◽  
Nathalie Davoust ◽  
Marianne Didier-Bazes ◽  
Carine Vuaillat ◽  
Christophe Malcus ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Subventricular Zone ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Cervical Lymph Nodes ◽  
The Central Nervous System ◽  
Anatomic Feature

AbstractThe lack of draining lymphatic vessels in the central nervous system (CNS) contributes to the so-called “CNS immune privilege.” However, despite such a unique anatomic feature, dendritic cells (DCs) are able to migrate from the CNS to cervical lymph nodes through a yet unknown pathway. In this report, labeled bone marrow-derived myeloid DCs were injected stereotaxically into the cerebrospinal fluid (CSF) or brain parenchyma of normal rats. We found that DCs injected within brain parenchyma migrate little from their site of injection and do not reach cervical lymph nodes. In contrast, intra-CSF-injected DCs either reach cervical lymph nodes or, for a minority of them, infiltrate the subventricular zone, where neural stem cells reside. Surprisingly, DCs that reach cervical lymph nodes preferentially target B-cell follicles rather than T-cell-rich areas. This report sheds a new light on the specific role exerted by CSF-infiltrating DCs in the control of CNS-targeted immune responses. (Blood. 2006; 107:806-812)

scholarly journals Review of a new concept of glaucoma pathogenesis based on the glymphatic theory of cerebrospinal fluid circulation

2020 ◽  
Vol 6 (3) ◽  
pp. 1-7
Author(s):  
Aleksandr A. Dolzhikov ◽  
Olga A. Shevchenko ◽  
Anna S. Pobeda ◽  
Anna A. Peresypkina ◽  
Irina N. Dolzhikova ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Optic Nerve ◽  
Ganglion Cells ◽  
Brain Parenchyma ◽  
Cribriform Plate ◽  
Fluid Circulation ◽  
Cerebrospinal Fluid Circulation ◽  
Glymphatic System ◽  
In Vivo Experiments

General aspects of glaucoma: Glaucoma is a heterogeneous multi-factorial disease that is one of the main causes of blindness, along with degeneration of retinal ganglion cells and optic nerve atrophy. Theories of pathogenesis: There are three theories of glaucoma pathogenesis: biomechanical, vascular, and biochemical. Basic theory of the glymphatic system: The classical knowledge of cerebrospinal fluid circulation has been revised, and in 2012 a new concept of glial-perivascular – glymphatic perfusion of the brain parenchyma was introduced. Due to experimental and clinical studies, it is approved by many scientists, especially in relation to Alzheimer’s disease (AD), in which amyloid pathology is the result of dysfunction of the para-/perivascular transport/cleansing pathways. Features of the optic nerve and the cribriform plate: The cribriform plate forms a barrier at the border of intraocular (IOP) and intracranial (ICP) pressures, thus affecting the para-/periarterial flow of cerebrospinal fluid to the optic nerve and retina, as well as the para-/perivenous cleansing outflow. Morphofunctional evidence of an ocular glymphatic system: The presence of an ocular glymphatic system is confirmed by in vivo experiments with the transfer of labeled substances through para-/perivascular structures from the ventricular or subarachnoid space to the optic nerve and by postmortem morphology. Clinical evidence for the glymphatic system hypothesis: There is some clinical, including case-based, and epidemiological evidence for similarities between glaucomatous optic nerve/retinal injuries and AD, since both occur in the form of improper secretion of neurotoxic metabolites, and both are often diagnosed together.

scholarly journals Leukocyte Recruitment in the Cerebrospinal Fluid of Mice with Experimental Meningitis Is Inhibited by an Antibody to Junctional Adhesion Molecule (Jam)

1999 ◽  
Vol 190 (9) ◽  
pp. 1351-1356 ◽  
Author(s):  
Aldo Del Maschio ◽  
Ada De Luigi ◽  
Ines Martin-Padura ◽  
Manfred Brockhaus ◽  
Tamas Bartfai ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Adhesion Molecule ◽  
Brain Parenchyma ◽  
Immunoglobulin Superfamily ◽  
Leukocyte Transmigration ◽  
Leukocyte Accumulation ◽  
Brain Barrier Permeability ◽  
The Brain

The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood–brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

scholarly journals Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases

2020 ◽  
Vol 29 (17) ◽  
pp. 2882-2898 ◽  
Author(s):  
Alan J Fowler ◽  
Michaeline Hebron ◽  
Kaluvu Balaraman ◽  
Wangke Shi ◽  
Alexander A Missner ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Therapeutic Target ◽  
Lewy Body Dementia ◽  
Protein Levels ◽  
Discoidin Domain Receptors ◽  
Discoidin Domain Receptor 1 ◽  
Complete Deletion

Abstract The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer’s and Parkinson’s disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.

scholarly journals Development and plasticity of meningeal lymphatic vessels

2017 ◽  
Vol 214 (12) ◽  
pp. 3645-3667 ◽  
Author(s):  
Salli Antila ◽  
Sinem Karaman ◽  
Harri Nurmi ◽  
Mikko Airavaara ◽  
Merja H. Voutilainen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Kinase Inhibitor ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Cerebrospinal Fluid Drainage ◽  
Lymphatic Endothelial Cells ◽  
Spinal Nerves ◽  
Adult Mice ◽  
The Central Nervous System

The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS.

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