Tegaserod Mimics the Neurostimulatory Glycan Polysialic Acid and Promotes Nervous System Repair

Overview

Journal Neuropharmacology

Specialties Neurology
Pharmacology

Date 2013 Sep 27

PMID 24067923

Citations 14

Authors

J Bushman

B Mishra

M Ezra

S Gul

C Schulze

S Chaudhury

D Ripoll

A Wallqvist

J Kohn

M Schachner

G Loers

Affiliations

Soon will be listed here.

Abstract

Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans.

Citing Articles

Biological function of sialic acid and sialylation in human health and disease.

Zhu W, Zhou Y, Guo L, Feng S Cell Death Discov. 2024; 10(1):415.

PMID: 39349440 PMC: 11442784. DOI: 10.1038/s41420-024-02180-3.

Small Organic Compounds Mimicking the Effector Domain of Myristoylated Alanine-Rich C-Kinase Substrate Stimulate Female-Specific Neurite Outgrowth.

Tschang M, Kumar S, Young W, Schachner M, Theis T Int J Mol Sci. 2023; 24(18).

PMID: 37762575 PMC: 10532424. DOI: 10.3390/ijms241814271.

Antagonistic L1 Adhesion Molecule Mimetic Compounds Inhibit Glioblastoma Cell Migration In Vitro.

Nagaraj V, Mikhail M, Baronio M, Gatto A, Nayak A, Theis T Biomolecules. 2022; 12(3).

PMID: 35327631 PMC: 8946856. DOI: 10.3390/biom12030439.

Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment.

Seguy L, Guyon L, Maurel M, Verdie P, Davis A, Corvaisier S Pharmaceutics. 2021; 13(10).

PMID: 34683919 PMC: 8540544. DOI: 10.3390/pharmaceutics13101626.

Functions of Small Organic Compounds that Mimic the HNK-1 Glycan.

Wang M, Theis T, Kabat M, Loers G, Agre L, Schachner M Int J Mol Sci. 2020; 21(19).

PMID: 32987628 PMC: 7582369. DOI: 10.3390/ijms21197018.

References

Kochlamazashvili G, Bukalo O, Senkov O, Salmen B, Gerardy-Schahn R, Engel A . Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors. J Neurosci. 2012; 32(7):2263-75. PMC: 6621799. DOI: 10.1523/JNEUROSCI.5103-11.2012. View

Kleene R, Yang H, Kutsche M, Schachner M . The neural recognition molecule L1 is a sialic acid-binding lectin for CD24, which induces promotion and inhibition of neurite outgrowth. J Biol Chem. 2001; 276(24):21656-63. DOI: 10.1074/jbc.M101790200. View

Mehanna A, Mishra B, Kurschat N, Schulze C, Bian S, Loers G . Polysialic acid glycomimetics promote myelination and functional recovery after peripheral nerve injury in mice. Brain. 2009; 132(Pt 6):1449-62. DOI: 10.1093/brain/awp128. View

Schiller L, Johnson D . Balancing drug risk and benefit: toward refining the process of FDA decisions affecting patient care. Am J Gastroenterol. 2008; 103(4):815-9. DOI: 10.1111/j.1572-0241.2008.01818.x. View

Berski S, van Bergeijk J, Schwarzer D, Stark Y, Kasper C, Scheper T . Synthesis and biological evaluation of a polysialic acid-based hydrogel as enzymatically degradable scaffold material for tissue engineering. Biomacromolecules. 2008; 9(9):2353-9. DOI: 10.1021/bm800327s. View

Phillips R, Wallace M, Lynch P, Hawk E, Gordon G, Saunders B . A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002; 50(6):857-60. PMC: 1773237. DOI: 10.1136/gut.50.6.857. View

Muller-Lissner S, Fumagalli I, Bardhan K, Pace F, Pecher E, Nault B . Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther. 2001; 15(10):1655-66. DOI: 10.1046/j.1365-2036.2001.01094.x. View

Haastert-Talini K, Schaper-Rinkel J, Schmitte R, Bastian R, Muhlenhoff M, Schwarzer D . In vivo evaluation of polysialic acid as part of tissue-engineered nerve transplants. Tissue Eng Part A. 2010; 16(10):3085-98. DOI: 10.1089/ten.TEA.2010.0180. View

Plane J, Shen Y, Pleasure D, Deng W . Prospects for minocycline neuroprotection. Arch Neurol. 2010; 67(12):1442-8. PMC: 3127230. DOI: 10.1001/archneurol.2010.191. View

10.

Irintchev A . Potentials and limitations of peripheral nerve injury models in rodents with particular reference to the femoral nerve. Ann Anat. 2011; 193(4):276-85. DOI: 10.1016/j.aanat.2011.02.019. View

11.

Loers G, Saini V, Mishra B, Papastefanaki F, Lutz D, Chaudhury S . Nonyloxytryptamine mimics polysialic acid and modulates neuronal and glial functions in cell culture. J Neurochem. 2013; 128(1):88-100. DOI: 10.1111/jnc.12408. View

12.

Franz C, Rutishauser U, Rafuse V . Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons. J Neurosci. 2005; 25(8):2081-91. PMC: 6726067. DOI: 10.1523/JNEUROSCI.4880-04.2005. View

13.

Finne J, Finne U, Goridis C . Occurrence of alpha 2-8 linked polysialosyl units in a neural cell adhesion molecule. Biochem Biophys Res Commun. 1983; 112(2):482-7. DOI: 10.1016/0006-291x(83)91490-0. View

14.

Yoder E, Tamir H, Ellisman M . 5-Hydroxytryptamine2A receptors on cultured rat Schwann cells. Glia. 1996; 17(1):15-27. DOI: 10.1002/(SICI)1098-1136(199605)17:1<15::AID-GLIA2>3.0.CO;2-6. View

15.

Petridis A, Wedderkopp H, Hugo H, Mehdorn H . Polysialic acid overexpression in malignant astrocytomas. Acta Neurochir (Wien). 2009; 151(6):601-3. DOI: 10.1007/s00701-009-0324-3. View

16.

Nicholson R, Small J, Dixon A, Spanswick D, Lee K . Serotonin receptor mRNA expression in rat dorsal root ganglion neurons. Neurosci Lett. 2003; 337(3):119-22. DOI: 10.1016/s0304-3940(02)01256-9. View

17.

Loers G, Chen S, Grumet M, Schachner M . Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis. J Neurochem. 2005; 92(6):1463-76. DOI: 10.1111/j.1471-4159.2004.02983.x. View

18.

Zhang Y, Zhang X, Wu D, Verhaagen J, Richardson P, Yeh J . Lentiviral-mediated expression of polysialic acid in spinal cord and conditioning lesion promote regeneration of sensory axons into spinal cord. Mol Ther. 2007; 15(10):1796-804. DOI: 10.1038/sj.mt.6300220. View

19.

Angata K, Fukuda M . Roles of polysialic acid in migration and differentiation of neural stem cells. Methods Enzymol. 2010; 479:25-36. DOI: 10.1016/S0076-6879(10)79002-9. View

20.

Zilkha-Falb R, Ziv I, Nardi N, Offen D, Melamed E, Barzilai A . Monoamine-induced apoptotic neuronal cell death. Cell Mol Neurobiol. 1997; 17(1):101-18. PMC: 11560161. DOI: 10.1023/a:1026333222008. View