A Peptide Targeting Inflammatory CNS Lesions in the EAE Rat Model of Multiple Sclerosis
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ORIGINAL ARTICLE
A Peptide Targeting Inflammatory CNS Lesions in the EAE Rat Model of Multiple Sclerosis Claudine Boiziau ,1,2,3,8 Macha Nikolski,4,5 Elodie Mordelet,1,2 Justine Aussudre,1,2 Karina Vargas-Sanchez,1,2,6 and Klaus G. Petry1,2,7
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. Due to the large diversity of sequences after phage display selection, a bioinformatics procedure called BPepTeam^ designed to identify peptides mimicking naturally occurring proteins was used, with the goal to predict peptides that were not background noise. We identified a circular peptide CLSTASNSC called BPh48^ as an efficient binder of inflammatory regions of EAE CNS sections including small inflammatory lesions of both white and gray matter. Tested on human brain endothelial cells hCMEC/D3, Ph48 was able to bind efficiently when these cells were activated with IL1β to mimic inflammatory conditions. The peptide is therefore a candidate for further analyses of the molecular alterations in inflammatory lesions.
Abstract—
KEY WORDS: marker of neuroinflammation; central nervous system; EAE; phage display; hCMEC/D3; blood brain barrier.
INTRODUCTION Multiple sclerosis (MS) is a neuroinflammatory disease with dispersed focal lesions causing myelin and neuronal loss throughout the central nervous system (CNS) [1, 2]. CNS 1
INSERM, UMR 1049, F-33076 Bordeaux, France Univ. Bordeaux, Neuroinflammation Imaging and Therapy of Multiple Sclerosis, F-33076 Bordeaux, France 3 Present Address: INSERM, UMR 1026, BioTis, F-33 076 Bordeaux, France 4 Univ. Bordeaux, CBiB, F-33076 Bordeaux, France 5 CNRS, LaBRI UMR 5800, F-33400 Talence, France 6 Present Address: Biomedical Sciences Research Group, GRINCIBIO, School of Medicine, Universidad Antonio Nariño, Bogotà, Colombia 7 Present Address: INSERM, UMR1029, F-33076 Bordeaux, France 8 To whom correspondence should be addressed at INSERM, UMR 1049, F-33076 Bordeaux, France. E-mail: [email protected] 2
lesions are mainly affecting the white matter with diffuse microscopic alterations around blood vessels [3]. In addition, MS assessment by MRI demonstrated atrophy of gray matter structures among which thalamus is one of the most differentially affected structures in volume, associated with specific pathophysiology of white matter lesions in MS [4]. In this way, it has been observed that thalamus could present early neurodegeneration with gray matter volume loss in MS due to disconnection caused by white matter lesions within thalamocortical projections [5]. The neuroinflammatory lesions are characterized by blood b
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