scholarly journals Targeting the Choroid Plexuses for Protein Drug Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 963
Author(s):  
Mark A. Bryniarski ◽  
Tianjing Ren ◽  
Abbas R. Rizvi ◽  
Anthony M. Snyder ◽  
Marilyn E. Morris
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
Protein Therapeutics ◽  
Ventricular System ◽  
Ependymal Cells ◽  
Choroid Plexuses ◽  
Choroid Plexus Epithelial

Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and ventricular system may be a surrogate brain delivery strategy to circumvent the blood-brain barrier. Heterogenous cell populations located at the choroid plexuses provide diverse functions in regulating the exchange of material within the ventricular space. Receptor-mediated transcytosis may be a promising mechanism to deliver protein therapeutics across the tight junctions formed by choroid plexus epithelial cells. However, cerebrospinal fluid flow and other barriers formed by ependymal cells and perivascular spaces should also be considered for evaluation of protein therapeutic disposition. Various preclinical methods have been applied to delineate protein transport across the choroid plexuses, including imaging strategies, ventriculocisternal perfusions, and primary choroid plexus epithelial cell models. When used in combination with simultaneous measures of cerebrospinal fluid dynamics, they can yield important insight into pharmacokinetic properties within the brain. This review aims to provide an overview of the choroid plexuses and ventricular system to address their function as a barrier to pharmaceutical interventions and relevance for central nervous system drug delivery of protein therapeutics. Protein therapeutics targeting the ventricular system may provide new approaches in treating central nervous system diseases.

Apparatus for long-term ventricular access in the awake canine

1986 ◽  
Vol 61 (1) ◽  
pp. 368-372 ◽  
Author(s):  
E. C. Ellison ◽  
T. T. Pappas ◽  
W. G. Pace ◽  
T. M. O'Dorisio
Keyword(s):  
Molecular Weight ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Peripheral Blood ◽  
Ventricular System ◽  
Blood Levels ◽  
Maximum Frequency ◽  
Fatal Complications

An apparatus is described that permits lateral ventricular cerebrospinal fluid (CSF) to be sampled or an infusion to be performed into the ventricular system in the awake canine. The device has been used in 25 dogs. CSF was sampled, and experiments involving infusions into the lateral ventricle were performed over a 6- to 24-mo period. The maximum frequency of ventricular cannulation using the apparatus was once per week. Complications occurred in 10 dogs, all of which were successfully treated, permitting experiments to continue. Three fatal complications included meningitis in one animal at 24 mo and seizures in two animals, causing death at 12 and 18 mo. Administration of peptides, bombesin, and somatostatin into the ventricular system was followed by prompt rises in bombesin and somatostatin radioimmunoactivity in the CSF. There were no parallel increases of these peptides in the peripheral blood levels up to 2 h after infusion. Peptides of this molecular weight infused with this apparatus do not seem to leak into peripheral blood. The apparatus permits repeated ventricular cannulation in the awake canine for sampling of CSF and administration of biological substances to determine specific central nervous system action.

Myo-inositol transport in the central nervous system

1975 ◽  
Vol 228 (5) ◽  
pp. 1510-1518 ◽  
Author(s):  
R Spector ◽  
AV Lorenzo
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
Intraventricular Injection ◽  
Affinity Constant ◽  
Rapid Injection ◽  
The Central Nervous System

Free myo-inositol (inositol) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the cerebrospinal fluid was measured in rabbits. In vivo, inositol transport from blood into choroid plexus, CSF, and brain was saturable with an apparent affinity constant (K-t) of approximately 0.1 mM. The relative turnover of free inositol in choroid plexus (16 percent/h) was higher than in CSF 4percent/h) and brain (0.3percent/h) when meausred by tissue penetration of tracer [3-H]-labeled inositol injected into blood. However, the passage of tracer inositol was not greater than the passage of mannitol into brain when measured 15 s after a rapid injection of inositol and mannitol into the left common carotid artery. From the CSF, the clearance of inositol relative to inulin was saturable after the intraventricular injection of various concentrations of inositol and inulin. Moreover, a portion of the inositol cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [3-H-labeled myo-inositol against a concentration gradient by a specific, active, saturable process with a K-t of 0.2 mM inositol. These results were interpreted as showing that the entry of inositol into the central nervous system from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

scholarly journals Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

2020 ◽  
Author(s):  
Daniela C. Ivan ◽  
Sabrina Walthert ◽  
Giuseppe Locatelli
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Choroid Plexus ◽  
Arginase 1 ◽  
Choroid Plexuses ◽  
Inflammatory Macrophages ◽  
Functional Polarization

ABSTRACTThe central nervous system (CNS) parenchyma is enclosed by anatomical interfaces including multilayered meninges, the blood-brain barrier (BBB), the choroid plexuses within ventricles and the glia limitans. These border areas hold distinct functional specializations which control the trafficking of monocyte-derived cells toward the CNS parenchyma, altogether maintaining CNS homeostasis. By crossing activated endothelial, epithelial and glial borders, circulating leukocytes gain however access to the CNS parenchyma in several inflammatory diseases including multiple sclerosis.Studies in animal models of neuroinflammation have helped describing the phenotypic specifications of these invading monocyte-derived cells, able to exert detrimental or beneficial functions depending on the local environment. In this context, in vivo visualization of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory macrophages has recently revealed that these distinct cell phenotypes are highly compartmentalized by CNS borders. While arginase-1+ macrophages densely populate the leptomeninges, iNOS+ macrophages rather accumulate in perivascular spaces and at the pia mater-CNS parenchymal interface.How and where these macrophages acquire their functional commitment, and whether differentially-activated monocyte-derived cells infiltrate the CNS through distinct gateways, remains however unclear.In this study, we have investigated the interaction of monocyte-derived macrophages with endothelial (BBB) and epithelial (choroid plexus) barriers of the CNS, both in vitro and in vivo. By using primary mouse brain microvascular endothelial cells as in vitro model of the BBB, we observed that, compared to unpolarized primary macrophages, adhesion of functionally-committed macrophages to endothelial cells was drastically reduced, literally abrogating their diapedesis across the BBB. Conversely, when interacting with an activated choroid plexus epithelium, both pro- and anti-inflammatory macrophages displayed substantial adhesive and migratory properties. Accordingly, in vivo analysis of choroid plexuses revealed increased macrophage trafficking and a scattered presence of polarized cells upon induction of anti-CNS inflammation.Altogether, we show that acquisition of distinct macrophage polarizations significantly alters the adhesive and migratory properties of these cells in a barrier-specific fashion. While monocytes trafficking at the level of the BBB seem to acquire their signature phenotype only following diapedesis, other anatomical interfaces can be the entry site for functionally activated monocyte-derived cells. Our study highlights the choroid plexus as a key access gateway for macrophages during neuroinflammation, and its stroma as a potential priming site for their functional polarization.

Fine Structure of the Lateral Area of the Posterior Rhombencephalic Tela of the Bullfrog, Rana Catesbiana

1980 ◽  
Vol 38 ◽  
pp. 522-523
Author(s):  
J. E. Michaels ◽  
P. A. Tornheim
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Subarachnoid Space ◽  
Fourth Ventricle ◽  
Essential Feature ◽  
Ventricular System ◽  
Ependymal Cells ◽  
Open Communication ◽  
Tela Choroidea ◽  
Lateral Area

In mammals, the caudal roof of the fourth ventricle consists of an inner layer of ependymal cells and an outer layer of leptomeningeal cells. It contains specializations in the form of tufts of choroid plexus for the elaboration of cerebrospinal fluid (CSF) as well as gross apertures that permit open communication between the ventricular system and the subarachnoid space, an essential feature for mammalian CSF circulation. In the bullfrog, as in most submammals, the roof of the fourth ventricle contains a rostral rhombencephalic choroid plexus with no gross evidence of fourth ventricular apertures. Communication between the ventricular system and the subarachnoid space in this animal, however, has been demonstrated to occur by way of microscopic openings or pores in the caudal roof of the hindbrain or the posterior rhombencephalic tela choroidea.

scholarly journals Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Kung ◽  
Kuan-Yu Chen ◽  
Wei-Hao Liao ◽  
Yi-Hua Hsu ◽  
Chueh-Hung Wu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Leptomeningeal Carcinomatosis ◽  
Low Energy ◽  
Penicillin G ◽  
The Central Nervous System ◽  
Energy Flux Density

Abstract Background The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases. Methods This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury. Results By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls. Conclusion This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.

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