scholarly journals The Pharmacology of Xenobiotics after Intracerebro Spinal Fluid Administration: Implications for the Treatment of Brain Tumors

2021 ◽  
Vol 22 (3) ◽  
pp. 1281
Author(s):  
Justine Paris ◽  
Eurydice Angeli ◽  
Guilhem Bousquet
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Metastasis ◽  
Poor Prognosis ◽  
Drug Distribution ◽  
Molecular Targets ◽  
Intrathecal Administration ◽  
Brain Parenchyma ◽  
Brain Distribution ◽  
Improvement In Survival ◽  
The Brain

The incidence of brain metastasis has been increasing for 10 years, with poor prognosis, unlike the improvement in survival for extracranial tumor localizations. Since recent advances in molecular biology and the development of specific molecular targets, knowledge of the brain distribution of drugs has become a pharmaceutical challenge. Most anticancer drugs fail to cross the blood–brain barrier. In order to get around this problem and penetrate the brain parenchyma, the use of intrathecal administration has been developed, but the mechanisms governing drug distribution from the cerebrospinal fluid to the brain parenchyma are poorly understood. Thus, in this review we discuss the pharmacokinetics of drugs after intrathecal administration, their penetration of the brain parenchyma and the different systems causing their efflux from the brain to the blood.

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 Mechanism of Coup and Contrecoup Injuries Induced by a Knock-Out Punch

2020 ◽  
Vol 25 (2) ◽  
pp. 22 ◽  
Author(s):  
Milan Toma ◽  
Rosalyn Chan-Akeley ◽  
Christopher Lipari ◽  
Sheng-Han Kuo
Keyword(s):  
Cerebrospinal Fluid ◽  
Interaction Model ◽  
Brain Parenchyma ◽  
Primary Objective ◽  
Element Analysis ◽  
Knock Out ◽  
Particle Hydrodynamics ◽  
Smoothed Particle ◽  
The Impact ◽  
The Brain

Primary Objective: The interaction of cerebrospinal fluid with the brain parenchyma in an impact scenario is studied. Research Design: A computational fluid-structure interaction model is used to simulate the interaction of cerebrospinal fluid with a comprehensive brain model. Methods and Procedures: The method of smoothed particle hydrodynamics is used to simulate the fluid flow, induced by the impact, simultaneously with finite element analysis to solve the large deformations in the brain model. Main Outcomes and Results: Mechanism of injury resulting in concussion is demonstrated. The locations with the highest stress values on the brain parenchyma are shown. Conclusions: Our simulations found that the damage to the brain resulting from the contrecoup injury is more severe than that resulting from the coup injury. Additionally, we show that the contrecoup injury does not always appear on the side opposite from where impact occurs.

scholarly journals Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

2019 ◽  
Author(s):  
Kevin Kleffman ◽  
Grace Levinson ◽  
Eitan Wong ◽  
Francisco Galán-Echevarría ◽  
Richard Von-Itter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Metastasis ◽  
Amyloid Beta ◽  
Metastatic Cancer ◽  
Melanoma Cells ◽  
Brain Parenchyma ◽  
Multiple Cancer ◽  
Cancer Types ◽  
The Brain

SummaryBrain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain.Here, we show that melanoma cells require amyloid beta (Aβ), a polypeptide heavily implicated in Alzheimer’s disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete Aβ, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of Aβ decreases brain metastatic burden.Our results reveal a mechanistic connection between brain metastasis and Alzheimer’s disease – two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.

scholarly journals Nanoparticle brain delivery: a guide to verification methods

Nanomedicine ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. 409-432 ◽  
Author(s):  
Robert A Yokel
Keyword(s):  
Cerebrospinal Fluid ◽  
Extracellular Space ◽  
Brain Parenchyma ◽  
Brain Delivery ◽  
Peripheral Organ ◽  
Blood Brain ◽  
Verification Methods ◽  
Brain Parenchymal ◽  
And Function ◽  
The Brain

Many reports conclude nanoparticle (NP) brain entry based on bulk brain analysis. Bulk brain includes blood, cerebrospinal fluid and blood vessels within the brain contributing to the blood–brain and blood–cerebrospinal fluid barriers. Considering the brain as neurons, glia and their extracellular space (brain parenchyma), most studies did not show brain parenchymal NP entry. Blood–brain and blood–cerebrospinal fluid barriers anatomy and function are reviewed. Methods demonstrating brain parenchymal NP entry are presented. Results demonstrating bulk brain versus brain parenchymal entry are classified. Studies are reviewed, critiqued and classified to illustrate results demonstrating bulk brain versus parenchymal entry. Brain, blood and peripheral organ NP timecourses are compared and related to brain parenchymal entry evidence suggesting brain NP timecourse informs about brain parenchymal entry.

scholarly journals Cerebrospinal Fluid and Interstitial Fluid Motion via the Glymphatic Pathway Modelled by Optimal Mass Transport

2016 ◽  
Author(s):  
Vadim Ratner ◽  
Yi Gao ◽  
Hedok Lee ◽  
Maikan Nedergaard ◽  
Helene Benveniste ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Interstitial Fluid ◽  
Initial Conditions ◽  
Fluid Motion ◽  
Flow Patterns ◽  
Brain Parenchyma ◽  
Fluid Exchange ◽  
Waste Products ◽  
Glymphatic Pathway ◽  
The Brain

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs [1,2]. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through peri-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach [3] to model the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

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 Kinetic Profile of the Transcriptome Changes Induced in the Choroid Plexus by Peripheral Inflammation

2009 ◽  
Vol 29 (5) ◽  
pp. 921-932 ◽  
Author(s):  
Fernanda Marques ◽  
João C Sousa ◽  
Giovanni Coppola ◽  
Ana M Falcao ◽  
Ana João Rodrigues ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Brain Parenchyma ◽  
Matrix Remodeling ◽  
Choroid Plexus Epithelial Cell ◽  
Blood Concentrations ◽  
The Brain

The choroid plexus, being part of the blood-brain barriers and responsible for the production of cerebrospinal fluid, is ideally positioned to transmit signals into and out of the brain. This study, using microarray analysis, shows that the mouse choroid plexus displays an acute-phase response after an inflammatory stimulus induced in the periphery by lipopolysaccharide (LPS). Remarkably, the response is specific to a restricted number of genes (out of a total of 24,000 genes analyzed, 252 are up-regulated and 173 are down-regulated) and transient, as it returns to basal conditions within 72 h. The up-regulated genes cluster into families implicated in immune-mediated cascades and in extracellular matrix remodeling, whereas those down-regulated participate in maintenance of the barrier function. Importantly, several acute-phase proteins, whose blood concentrations rise in response to inflammation, may contribute to the effects observed in vivo after LPS injection, as suggested by the differential response of primary choroid plexus epithelial cell cultures to LPS alone or to serum collected from animals exposed to LPS. By modulating the composition of the cerebrospinal fluid, which will ultimately influence the brain parenchyma, the choroid plexus response to inflammation may be of relevance in brain homeostasis in health and disease.

scholarly journals Is Vagus Nerve Stimulation Brain Washing?

2019 ◽  
Author(s):  
Kevin P. Cheng ◽  
Sarah K. Brodnick ◽  
Stephan L. Blanz ◽  
Weifeng Zeng ◽  
Jack Kegel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Intractable Epilepsy ◽  
Brain Parenchyma ◽  
Vagal Nerve ◽  
Waste Products ◽  
Adrenergic Signaling ◽  
The Brain

AbstractVagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.One Sentence SummaryCervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.

Massive Brain Swelling after Cranioplasty: A Case Report

2019 ◽  
Vol 80 (06) ◽  
pp. 498-502
Author(s):  
Xiaoyang Zhang ◽  
Baogen Pan ◽  
Zhanying Ye ◽  
Zheng Li ◽  
Feng Mo ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Ct Scan ◽  
Poor Prognosis ◽  
Lessons Learned ◽  
Brain Swelling ◽  
Common Procedure ◽  
Brain Computed Tomography ◽  
Risk Patients ◽  
Lumbar Cerebrospinal Fluid ◽  
The Brain

Abstract Background Cranioplasty is a common procedure in neurosurgery. It is usually performed following decompressive craniectomy (DC). However, complications may occur after the operation, such as massive brain swelling. Up to now, far too little attention has been given to this severe complication. We report one case of fatal cerebral swelling after cranioplasty and analyze the possible mechanism of this complication. Case Description The patient was a 40-year-old man who had a severe right basal ganglia cerebral hemorrhage and underwent DC ∼ 2 months before. One day before scheduled cranioplasty, a lumbar cerebrospinal fluid drainage was placed. The cranioplasty itself was uneventful. However, he gradually fell into a coma, and his right pupil was moderately dilated 20 hours after the surgery. A brain computed tomography (CT) scan indicated massive right cerebral edema with compressed right midbrain. The patient did not regain consciousness, and he remained quadriplegic. Conclusion It is necessary to increase awareness of complications of cranioplasty in high-risk patients. The lessons learned from this case include avoiding excessive drainage of cerebrospinal fluid. Patients with low-density lesions in the brain need to be treated with caution. Once the CT scan shows massive cerebral swelling, the patient has a poor prognosis.

Membrane structure in mammalian astrocytes: a review of freeze-fracture studies on adult, developing, reactive and cultured astrocytes

1981 ◽  
Vol 95 (1) ◽  
pp. 35-48
Author(s):  
D. M. Landis ◽  
T. S. Reese
Keyword(s):  
Cerebrospinal Fluid ◽  
Membrane Structure ◽  
Plasma Membranes ◽  
Freeze Fracture ◽  
Brain Parenchyma ◽  
Specific Pattern ◽  
Cultured Astrocytes ◽  
Fluid Compartments ◽  
Polygonal Particle ◽  
The Brain

The application of freeze-fracture techniques to studies of brain structure has led to the recognition of two unsuspected specializations of membrane structure, each distributed in a specific pattern across the surface of astrocytes. ‘Assemblies’ (aggregates of uniform, small particles packed in orthogonal array into rectangular or square aggregates) are found to characterize astrocytic plasma membranes apposed to blood vessels or to the cerebrospinal fluid at the surface of the brain. These particle aggregates are much less densely packed in astrocytic processes in brain parenchyma. Assemblies are not fixation artifacts, have been shown to extend to the true outer surface of the membrane, are remarkably labile in the setting of anoxia, and are at least in part protein. The function of assemblies is unknown, but their positioning suggests that they may have a role in the transport of some material into or out of the blood and cerebrospinal fluid compartments. A second specialization of intramembrane particle distribution, the polygonal particle junction, links astrocytic processes at the surface of the brain, and also links proximal, large caliber astrocytic processes in brain parenchyma. The function of this membrane specialization also is unknown, but it may subserve a mechanical role.

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