A polysialic acid mimetic peptide promotes functional recovery in a mouse model of spinal cord injury

• Published in: Experimental neurology 2009-09, Vol.219 (1), p.163-174
• Main Authors: Marino, Philippe, Norreel, Jean-Chrétien, Schachner, Melitta, Rougon, Geneviève, Amoureux, Marie-Claude
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Axons - drug effects; Axons - metabolism; Axons - ultrastructure; Biological and medical sciences; Cells, Cultured; Cellular Biology; Denervation; Disease Models, Animal; Extracellular Matrix - metabolism; Glial Fibrillary Acidic Protein - metabolism; Glial scar; Gliosis - drug therapy; Gliosis - pathology; Gliosis - physiopathology; Injuries of the nervous system and the skull. Diseases due to physical agents; Life Sciences; Medical sciences; Mice; Mimetic peptide; Neural Cell Adhesion Molecule L1 - metabolism; Neural Cell Adhesion Molecules - drug effects; Neural Cell Adhesion Molecules - metabolism; Neurology; Peptides - chemistry; Peptides - pharmacology; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Polysialic acid-NCAM; Rats; Rats, Wistar; Recovery of Function - drug effects; Recovery of Function - physiology; SCI improvement; Serotonergic neurons; Serotonin - metabolism; Sialic Acids - agonists; Sialic Acids - metabolism; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - physiopathology; Spinal cord injury; Traumas. Diseases due to physical agents
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2009.05.009

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.