The polysialic acid mimetics 5-nonyloxytryptamine and vinorelbine facilitate nervous system repair

Abstract

Polysialic acid (PSA) is a large negatively charged glycan mainly attached to the neural cell adhesion molecule (NCAM). Several studies have shown that it is important for correct formation of brain circuitries during development and for synaptic plasticity, learning and memory in the adult. PSA also plays a major role in nervous system regeneration following injury. As a next step for clinical translation of PSA based therapeutics, we have previously identified the small organic compounds 5-nonyloxytryptamine and vinorelbine as PSA mimetics. Activity of 5-nonyloxytryptamine and vinorelbine had been confirmed in assays with neural cells from the central and peripheral nervous system in vitro and shown to be independent of their function as serotonin receptor 5-HT1B/1D agonist or cytostatic drug, respectively. As we show here in an in vivo paradigm for spinal cord injury in mice, 5-nonyloxytryptamine and vinorelbine enhance regain of motor functions, axonal regrowth, motor neuron survival and remyelination. These data indicate that 5-nonyloxytryptamine and vinorelbine may be re-tasked from their current usage as a 5-HT1B/1D agonist or cytostatic drug to act as mimetics for PSA to stimulate regeneration after injury in the mammalian nervous system.

5‐Nonyloxytryptamine oxalate–embedded collagen–laminin scaffolds augment functional recovery after spinal cord injury in mice

“…In our previous study, application of 5‐NOT during the acute phase of SCCI, but without any biomaterial base, improved the locomotor function in mice by approximately 80% 8 weeks after injury . Using a similar paradigm, but delivered together with C/L hydrogels, 5‐NOT could improve the locomotor function in mice by 75% 2 weeks after injury.…”

“…It is also considered the cardinal molecule for structural, functional, and synaptic plasticity of the adult nervous system . In order to exploit the vast therapeutic potential of PSA, previous studies have focused on the identification and development of peptide‐based or synthetic PSA mimetics . In a previous study, we observed ∼80% gain of locomotor function in mice after 8 weeks of a single intraoperative application of a synthetic PSA mimetic 5‐nonyloxytryptamine (5‐NOT) following spinal cord compression injury (SCCI) …”

Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria

“…Polysialylation of NCAM is involved in neural plasticity and learning and memory processes. The modulation of the polysialylation has been discussed for the treatment of different neurodegenerative diseases and as general tool for neuro‐regeneration . Reduced polysialylation has been described for patients with Parkinson's and Alzheimer's diseases and in schizophrenia .…”

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

“…Here, we summarize a group of natural products (including semisynthetic compounds) that functionally mimic glycans, have proven neuroprotective functions, and may therefore form a novel class of therapeutics for NDs. These "natural glycomimetics" are classified based on the glycans they mimic including human natural killer-1 (HNK-1) [140], LewisX (LeX) [141], neural cell adhesion molecule L1 (L1CAM) [142], and polysialic acid (PSA) [143]. The glycan-mimicking properties of these compounds have been confirmed by competitive enzyme-linked immunosorbent assay (ELISA) using glycan antibodies.…”

“…However, at lower concentrations, it can block mitotic progression at the G2-M phase [177]. Recent studies also indicate that vinorelbine can functionally mimic PSA and promote neurite outgrowth through regulation of myristoylated alanine-rich C kinase substrate, NCAM, and fibroblast growth factor receptor via Erk signaling [143].…”