Tegaserod, a small compound mimetic of polysialic acid, promotes functional recovery after spinal cord injury in mice.

Abstract

In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. In the present study, a mouse spinal cord compression device was used to elicit severe compression injury. We show that tegaserod promotes hindlimb motor function at 6 weeks after spinal cord injury compared to the control group receiving vehicle only. Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates.

• Authors: H-C Pan, Y-Q Shen, G Loers, I Jakovcevski, M Schachner
• Journal: Neuroscience (Neuroscience) Vol. 277 Pg. 356-66 (Sep 26 2014) ISSN: 1873-7544 [Electronic] United States
• PMID: 25014876 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Glial Fibrillary Acidic Protein
• Indoles
• Nerve Tissue Proteins
• Neuroprotective Agents
• glial fibrillary astrocytic protein, mouse
• Serotonin
• tegaserod
• Tyrosine 3-Monooxygenase

Topics

• Animals
• Astrocytes (drug effects, pathology, physiology)
• Axons (drug effects, pathology, physiology)
• Cell Count
• Cell Survival (drug effects)
• Cicatrix (drug therapy, pathology, physiopathology)
• Disease Models, Animal
• Female
• Glial Fibrillary Acidic Protein
• Gliosis (drug therapy, pathology, physiopathology)
• Hindlimb (physiopathology)
• Indoles (pharmacology)
• Mice, Inbred C57BL
• Motor Activity (drug effects, physiology)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (pharmacology)
• Recovery of Function (drug effects, physiology)
• Serotonin (metabolism)
• Spinal Cord (drug effects, pathology, physiopathology)
• Spinal Cord Injuries (drug therapy, pathology, physiopathology)
• Tyrosine 3-Monooxygenase (metabolism)