Chronic neurodegenerative diseases are characterized by substantial inflammation with putative impairment of the brain vasculature also commonly observed. To address effects of chronic neurodegeneration on the regional vasculature under experimentally controlled circumstances, the glutamate receptor agonist ibotenic acid was injected into striatum of adult rats, which causes excitotoxicity in the substantia nigra pars reticulata (SNpr) due to imbalance between inhibitory inputs from the striatum and excitatory signals from the subthalamic nucleus. Brains were examined at 28 days (short-term neurodegeneration) and 91 days (long-term neurodegeneration) and analyzed for vascular remodeling taking both 2D and 3D approaches, the latter involving confocal microscopy of optically cleared samples combined with machine learning-based image analysis.
View Article and Find Full Text PDFNeurodegenerative diseases are often accompanied by neuroinflammation and impairment of the blood-brain barrier (BBB) mediated by activated glial cells through their release of proinflammatory molecules. To study the effects of glial cells on mouse brain endothelial cells (mBECs), we developed an in vitro BBB model with inflammation by preactivating mixed glial cells (MGCs) with lipopolysaccharide (LPS) before co-culturing with mBECs to study the influence of molecules released by activated MGCs. The response of the mBECs to activated MGCs was compared to direct stimulation with LPS.
View Article and Find Full Text PDFBackground: Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries using the histone deacetylase inhibitor (HDACi) valproic acid (VPA).
Methods: Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA.
Expert Opin Drug Deliv
January 2024
Introduction: The treatment of neurological diseases is significantly hampered by the lack of available therapeutics. A major restraint for the development of drugs is denoted by the presence of the blood-brain barrier (BBB), which precludes the transfer of biotherapeutics to the brain due to size restraints.
Areas Covered: Novel optimism for transfer of biotherapeutics to the brain has been generated via development of targeted therapeutics to nutrient transporters expressed by brain capillary endothelial cells (BCECs).
The use of therapeutic antibodies for treating diseases in the CNS is hampered by the blood-brain barrier (BBB). In this issue, Edavettal et al. report on a novel bioengineered antibody not only capable of passing the BBB but also for intervening in pathological protein deposition and subsequent induction of clearing by microglia.
View Article and Find Full Text PDFOverexpression of α-synuclein with tyrosine mutated to phenylalanine at position 125 leads to a severe phenotype with motor impairment and neuropathology in . Here, we hypothesized that tyrosine mutations would similarly lead to impaired motor performance with neuropathology in a rodent model. In transgenic mice (ASO), tyrosines at positions 125, 133, and 136 in human α-synuclein were mutated to phenylalanine and cloned into a Thy1.
View Article and Find Full Text PDFThe blood-brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation.
View Article and Find Full Text PDFIntroduction: Temporary twenty-four-hour accommodations (TTAs) are municipal beds for elderly patients discharged from the hospital with acute treatment, care and/or rehabilitation needs that cannot be met in their own homes. TTAs are staffed by nurses and nursing assistants who are not authorized to prescribe or modify medications. At North Zealand Hospital one third of the many readmissions from a TTA within eight days after discharge have been assessed as preventable.
View Article and Find Full Text PDFBrain homeostasis depends on the existence of the blood-brain barrier (BBB). Despite decades of research, the factors and signalling pathways for modulating and maintaining BBB integrity are not fully elucidated. Here, we characterise the expression and function of the multifunctional receptor, sortilin, in the cells of the BBB, in vivo and in vitro.
View Article and Find Full Text PDFThe blood-brain barrier (BBB) is formed by brain capillary endothelial cells (BECs) supported by pericytes and astrocytes. The BBB maintains homeostasis and protects the brain against toxic substances circulating in the blood, meaning that only a few drugs can pass the BBB. Thus, for drug screening, understanding cell interactions, and pathology, in vitro BBB models have been developed using BECs from various animal sources.
View Article and Find Full Text PDFBackground: There is a paucity of research describing the gait pattern of lame horses at the walk.
Objectives: To describe the changes in motion pattern and vertical ground reaction forces (GRFz) in horses with induced forelimb lameness at the walk and compare those changes with the changes observed at the trot.
Study Design: Experimental study.
Neurodegeneration is associated with inflammation and mismanaged iron homeostasis, leading to increased concentration of non-transferrin-bound iron (NTBI) in the brain. NTBI can be taken up by cells expressing Zrt-, Irt-like protein-14 (ZIP14), which is regulated by iron overload and pro-inflammatory cytokines, for example, interleukin-1β (IL-1β) and IL-6. Here, we focus on the astrocytic involvement and regulation of ZIP14 in an experimental model of chronic neurodegeneration with inflammation and iron overload.
View Article and Find Full Text PDFTransport of the majority of therapeutic molecules to the brain is precluded by the presence of the blood-brain barrier (BBB) rendering efficient treatment of many neurological disorders impossible. This BBB, nonetheless, may be circumvented by targeting receptors and transport proteins expressed on the luminal surface of the brain capillary endothelial cells (BCECs). The transferrin receptor (TfR) has remained a popular target since its original description for this purpose, although clinical progression of TfR-targeted drug constructs or nanomedicines remains unsuccessful.
View Article and Find Full Text PDFThe ability to treat invalidating neurological diseases is impeded by the presence of the blood-brain barrier (BBB), which inhibits the transport of most blood-borne substances into the brain parenchyma. Targeting the transferrin receptor (TfR) on the surface of brain capillaries has been a popular strategy to give a preferential accumulation of drugs or nanomedicines, but several aspects of this targeting strategy remain elusive. Here we report that TfR-targeted gold nanoparticles (AuNPs) can accumulate in brain capillaries and further transport across the BBB to enter the brain parenchyma.
View Article and Find Full Text PDFJ Cereb Blood Flow Metab
October 2017
The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes.
View Article and Find Full Text PDFThe brain vascular basement membrane is important for both blood-brain barrier (BBB) development, stability, and barrier integrity and the contribution hereto from brain capillary endothelial cells (BCECs), pericytes, and astrocytes of the BBB is probably significant. The aim of this study was to analyse four different in vitro models of the murine BBB for expression and possible secretion of major basement membrane proteins from murine BCECs (mBCECs). mBCECs, pericytes and glial cells (mainly astrocytes and microglia) were prepared from brains of C57BL/6 mice.
View Article and Find Full Text PDFBrain capillary endothelial cells denote the blood-brain barrier (BBB), and conjugation of nanoparticles with antibodies that target molecules expressed by these endothelial cells may facilitate their uptake and transport into the brain. Magnetic nanoparticles can be encapsulated in liposomes and carry large molecules with therapeutic potential, for example, siRNA, cDNA and polypeptides. An additional approach to enhance the transport of magnetic nanoparticles across the BBB is the application of extracranially applied magnetic force.
View Article and Find Full Text PDFBackground: Primary brain capillary endothelial cells (BCECs) are a promising tool to study the blood-brain barrier (BBB) in vitro, as they maintain many important characteristics of the BBB in vivo, especially when co-cultured with pericytes and/or astrocytes. A novel strategy for drug delivery to the brain is to transform BCECs into protein factories by genetic modifications leading to secretion of otherwise BBB impermeable proteins into the central nervous system. However, a huge challenge underlying this strategy is to enable transfection of non-mitotic BCECs, taking a non-viral approach.
View Article and Find Full Text PDFChronic inflammation in the substantia nigra (SN) accompanies conditions with progressive neurodegeneration. This inflammatory process contributes to gradual iron deposition that may catalyze formation of free-radical mediated damage, hence exacerbating the neurodegeneration. This study examined proteins related to iron-storage (ferritin) and iron-export (ferroportin) (aka metal transporter protein 1, MTP1) in a model of neurodegeneration.
View Article and Find Full Text PDFThis study aimed to create an evidence base for detection of stance-phase timings from motion capture in horses. The objective was to compare the accuracy (bias) and precision (SD) for five published algorithms for the detection of hoof-on and hoof-off using force plates as the reference standard. Six horses were walked and trotted over eight force plates surrounded by a synchronised 12-camera infrared motion capture system.
View Article and Find Full Text PDFThe objective of the present study was to explore the potential of using an in situ suspension forming drug delivery system of celecoxib to provide sustained drug exposure in the joint cavity following intra-articular administration. In vitro, precipitates were formed upon addition of a 400 mg/mL solution of celecoxib in polyethylene glycol 400 (PEG 400) to phosphate buffer, pH 7.4, or synovial fluid.
View Article and Find Full Text PDFObjective: To describe the pharmacokinetics of intra-articularly (IA) administered morphine.
Study Design: Experimental randomized, cross-over study.
Animals: Eight adult healthy mixed breed horses aged 6.
Objective: To compare the analgesic effect of intra-articular (IA) and intravenous (IV) morphine in horses with experimentally induced synovitis.
Animals: Eight adult horses.
Study Design: Randomized, observer blinded, double dummy trial with sequential crossover design.
Objective: To compare the effects of intra-articular (IA) versus IV administration of morphine on local and systemic inflammatory responses in horses with experimentally induced acute synovitis.
Animals: 8 horses.
Procedures: Each horse received the following 2 treatments 4 hours after synovitis was induced: IA administration of morphine (0.