Specific nanoprobe design for MRI: Targeting laminin in the blood-brain barrier to follow alteration due to neuroinflammation.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations.

Comparative Evaluation of Reproducibility of Phage-Displayed Peptide Selections and NGS Data, through High-Fidelity Mapping of Massive Peptide Repertoires.

Phage-displayed peptide selections generate complex repertoires of several hundred thousand peptides as revealed by next-generation sequencing (NGS). In repeated peptide selections, however, even in identical experimental in vitro conditions, only a very small number of common peptides are found. The repertoire complexities are evidence of the difficulty of distinguishing between effective selections of specific peptide binders to exposed targets and the potential high background noise.

Screening for Interacting Proteins with Peptide Biomarker of Blood-Brain Barrier Alteration under Inflammatory Conditions.

Neurodegenerative diseases are characterized by increased permeability of the blood-brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions.

Brain-Immune Interactions and Neuroinflammation After Traumatic Brain Injury.

Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients.

A Computational Pipeline for the Extraction of Actionable Biological Information From NGS-Phage Display Experiments.

Phage Display is a powerful method for the identification of peptide binding to targets of variable complexities and tissues, from unique molecules to the internal surfaces of vessels of living organisms. Particularly for screenings, the resulting repertoires can be very complex and difficult to study with traditional approaches. Next Generation Sequencing (NGS) opened the possibility to acquire high resolution overviews of such repertoires and thus facilitates the identification of binders of interest.

A Peptide Targeting Inflammatory CNS Lesions in the EAE Rat Model of Multiple Sclerosis.

Multiple sclerosis is characterized by inflammatory lesions dispersed throughout the central nervous system (CNS) leading to severe neurological handicap. Demyelination, axonal damage, and blood brain barrier alterations are hallmarks of this pathology, whose precise processes are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) rat model that mimics many features of human multiple sclerosis, the phage display strategy was applied to select peptide ligands targeting inflammatory sites in CNS.

DNA Subtraction of In Vivo Selected Phage Repertoires for Efficient Peptide Pathology Biomarker Identification in Neuroinflammation Multiple Sclerosis Model.

To streamline in vivo biomarker discovery, we developed a suppression subtractive DNA hybridization technique adapted for phage-displayed combinatorial libraries of 12 amino acid peptides (PhiSSH). Physical DNA subtraction is performed in a one-tube-all-reactions format by sequential addition of reagents, producing the enrichment of specific clones of one repertoire. High-complexity phage repertoires produced by in vivo selections in the multiple sclerosis rat model (experimental autoimmune encephalomyelitis, EAE) and matched healthy control rats were used to evaluate the technique.

Development of a solvent-free analytical method for paracetamol quantitative determination in Blood Brain Barrier in vitro model.

A Reversed Phase-High Performance Liquid Chromatography/Diode Array Detection method was developed and validated for paracetamol quantification in cell culture fluid from an in vitro Blood Brain Barrier model. The chromatographic method and sample preparation were developed using only aqueous solvents. The column was a XTerra RP18 150 × 4.

Aquaporin and brain diseases.

Background: The presence of water channel proteins, aquaporins (AQPs), in the brain led to intense research in understanding the underlying roles of each of them under normal conditions and pathological conditions.

Scope Of Review: In this review, we summarize some of the recent knowledge on the 3 main AQPs (AQP1, AQP4 and AQP9), with a special focus on AQP4, the most abundant AQP in the central nervous system.

Major Conclusions: AQP4 was most studied in several brain pathological conditions ranging from acute brain injuries (stroke, traumatic brain injury) to the chronic brain disease with autoimmune neurodegenerative diseases.

Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging.

Purpose: To compare magnetic resonance (MR) imaging features of multiple sclerosis (MS) lesions after the administration of a gadolinium-based contrast agent and ultrasmall superparamagnetic iron oxide (USPIO) particles among the clinical phenotypes of MS and over time.

Materials And Methods: This study was approved by the local ethics committee, and written informed consent was obtained from all patients. Twenty-four patients with MS (10 with relapsing and 14 with progressive forms) underwent clinical and gadolinium- and USPIO-enhanced MR examinations at baseline and 6-month follow-up.

Differential aquaporin 4 expression during edema build-up and resolution phases of brain inflammation.

Background: Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood.

Adapted focal experimental autoimmune encephalomyelitis to allow MRI exploration of multiple sclerosis features.

We aimed to determine an optimal protocol for inducing a focal inflammatory lesion within the rat brain that could be large enough for an easier MRI monitoring while still relevant as a multiple sclerosis (MS) like lesion. We adapted a two-hit model based on pre-sensitization of the Lewis rat with myelin oligodendrocyte protein (MOG) followed by stereotaxic injection of pro-inflammatory cytokines (TNFα+IFNγ) within the internal capsule. We compared the following two strategies to increase focal lesion development for an easier MR translation: (1) a higher sensitization step (MOG50) or (2) a higher cytokine step with lower sensitization (MOG25).

Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration.

Objectives: We investigated proinflammatory M1 and immunomodulatory M2 activation profiles of circulating monocytes in relapsing experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, and tested whether altered M1/M2 equilibrium promotes CNS inflammation.

Results: Approaches of MRI macrophage tracking with USPIO nanoparticles and expression patterns of M1/M2 macrophages and microglia in brain and M1/M2 monocytes in blood samples at various disease stages revealed that M1/M2 equilibrium in blood and CNS favors mild EAE, while imbalance towards M1 promotes relapsing EAE. We consequently investigated whether M2 activated monocyte restoration in peripheral blood could cure acute clinical EAE disease.

Inflammation induced neurological handicap processes in multiple sclerosis: new insights from preclinical studies.

Multiple sclerosis (MS) is described as originating from incompletely explained neuroinflammatory processes, dysfunction of neuronal repair mechanisms and chronicity of inflammation events. Blood-borne immune cell infiltration and microglia activation are causing both neuronal destruction and myelin loss, which are responsible for progressive motor deficiencies, organic and cognitive dysfunctions. MRI as a non-invasive imaging method offers various ways to visualise de- and remyelination, neuronal loss, leukocyte infiltration, blood-brain barrier modification and new sensors are emerging to detect inflammatory lesions at an early stage.

Type 3 deiodinase expression in inflammatory spinal cord lesions in rat experimental autoimmune encephalomyelitis.

Background: We have shown substantial expression of type 3 deiodinase (D3, a major enzyme involved in the inactivation of thyroid hormone) in infiltrating leukocytes in several models of inflammation. Recently, thyroid hormone has been shown to improve remyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. As induction of D3 may play an important role in decreasing local bioavailability of thyroid hormone at inflammation sites, we hypothesized that D3 is induced in spinal cord inflammatory lesions in EAE.

Annexin A5-functionalized liposomes for targeting phosphatidylserine-exposing membranes.

Long-circulating liposomes functionalized with cell-targeting elements and loaded with bioactive compounds present high interest as drug delivery nanosystems. We present here the synthesis and physicochemical characterization of liposomes containing PEGylated lipids covalently linked to oriented Annexin-A5 (Anx5) proteins, and we show that Anx5-functionalized liposomes are able to target phosphatidylserine (PS)-exposing membranes. The covalent coupling of Anx5 to liposomes is almost quantitative, which is mainly due to the high accessibility of the reacting groups.

Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain: a combined MRI-histological study.

Hydrocephalus features include ventricular dilatation and periventricular edema due to transependymal resorption of cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a water channel protein located at the blood-brain barrier, might facilitate the removal of this excess of water from the parenchyma into the blood. First, we hypothesized a link between AQP4 expression and the severity of hydrocephalus.

Pain and quality of life in the early stages after multiple sclerosis diagnosis: a 2-year longitudinal study.

Background: Pain is a frequent symptom during the course of multiple sclerosis (MS) but its frequency and impact at the early clinical stages remain unknown.

Objectives: The aim of this study was to establish prevalence and severity of pain in a cohort of patients recently diagnosed with MS and to determine the evolution of pain prevalence over 2 years. Other objectives were to investigate the presence of baseline clinical predictors of pain after 2 years and to establish its impact on quality of life (QOL).

Monitoring demyelination and remyelination by magnetization transfer imaging in the mouse brain at 9.4 T.

Objective: The aim of this study was to assess quantitatively structural changes in myelin content occurring during demyelination and remyelination by magnetization transfer imaging (MTI).

Materials And Methods: In a reversible model of demyelination with no axonal loss, mice intoxicated by cuprizone were studied by MTI in vivo at 9.4 T.

How to trace stem cells for MRI evaluation?

Applications of imaging techniques to visualize stem cells for monitoring, control and treatment of biological systems, in particular the brain, is at the forefront of investigations. These approaches involve the identification of stem and precursor cells that may be of various origins, but are related to specific clinical conditions, and the choice of the appropriate markers to achieve the required imaging while minimizing the side effects. This article will review examples of the contrast agent design for rational approaches in stem cell imaging.

Magnetic resonance imaging of human brain macrophage infiltration.

Macrophage tracking by magnetic resonance imaging (MRI) with iron oxide nanoparticles has been developed during the last decade for numerous diseases of the CNS. Experimental studies on animal models were confirmed by first clinical applications of MRI technology of brain macrophages for multiple sclerosis, ischemic stroke lesions, and tumors. As activated macrophages act in concert with other immune competent cells, this innovative MRI approach provides new functional data on the immune reaction in these CNS diseases.

Characterization and restoration of altered inhibitory and excitatory control of micturition reflex in experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is characterized by inflammatory lesions throughout the central nervous system. Spinal cord inflammation correlates with many neurological defecits. Most MS patients suffer from micturition dysfunction with urinary incontinence and difficulty in emptying the bladder.