A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury.
Contrary to lower species that recapitulate some of the developmental programs, in mammals, functional recovery after spinal cord injury is impaired by a non-permissive environment and the lack of plasticity of adult neurons. The developmental plasticity associated linear homopolymer of alpha 2,8-linked sialic acid (PolySialic Acid, PSA), represents a permissive determinant that could contribute to recovery. We previously showed that a PSA cyclic mimetic peptide (PR-21) displayed PSA-like biological functions (Torregrossa, P., Buhl, L., Bancila, M., Durbec, P., Schafer, C., Schachner, M., Rougon, G., 2004. Selection of poly-alpha 2,8-sialic acid mimotopes from a random phage peptide library and analysis of their bioactivity. J. Biol. Chem. 279, 30707-30714.). In the present study we investigated the therapeutic potential of PR-21 in young adult mice after dorsal hemisection at the T9 level. We show that PR-21 fulfills several criteria for an in vivo use as it is not toxic, not immunogenic and displays good stability in biological fluids or tissue. Delivery of PR-21 to the lesion site decreased the time of the animals' return to continence, and enhanced motor functions, sensorimotor control and coordination of hindlimbs with forelimbs when compared to a control peptide. At the cellular level, PR-21 increased serotonergic axon density at and caudal to the lesion site, and decreased reactive gliosis in vivo. In an in vitro model of reactive astrocytes, PR-21 increased NCAM expression in strongly GFAP positive cells. Our data point to the unique features of a carbohydrate mimicking peptide, and support the notion that PSA can be considered as an important factor in recovery from spinal cord injury.
Marino
Philippe
P
Institut de Biologie du Développement de Marseille-Luminy (IBDML), Université de la Méditerranée CNRS 6216, Parc Scientifique de Luminy, 13288 Marseille Cedex 09, France.
Norreel
Jean-Chrétien
JC
Schachner
Melitta
M
Rougon
Geneviève
G
Amoureux
Marie-Claude
MC
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D003714:Denervation; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D012794:Sialic Acids / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D005904:Glial Fibrillary Acidic Protein; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; C543816:PR-21 cyclic peptide; D010455:Peptides; D010456:Peptides, Cyclic; D012794:Sialic Acids; C021319:polysialic acid; C103469:polysialyl neural cell adhesion molecule; D012701:Serotonin