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

Abstract

Polysialic acid (PSA) is crucial for the induction and maintenance of nervous system plasticity and repair after injury. In order to exploit the immense therapeutic potential of PSA, previous studies have focused on the identification and development of peptide‐based or synthetic PSA mimetics. 5‐Nonyloxytryptamine (5‐NOT) has been previously reported as a PSA‐mimicking compound for promoting functional recovery after spinal cord injury in mice. In order to explore the neuroregeneration potential of 5‐NOT, the current study was based on a biomaterial approach using collagen–laminin (C/L) scaffolds. In in vitro studies, 5‐NOT was observed to promote neurite outgrowth, migration, and fasciculation in cerebellar neuronal cells, whereas in 3D cell cultures it showed more ramification and complex Sholl profiles. 5‐NOT promoted the survival and neurite length of cortical neurons when cocultured with glutamate‐challenged astrocytes. In in vivo studies, spinal cord compression injury mice were used with immediate application of C/L hydrogels impregnated with 5‐NOT. C/L + 5‐NOT–treated mice demonstrated ∼75% of motor recovery 14 days after injury. Furthermore, this effect was shown to be dependent on the ERK–MAPK pathway and augmentation of cell survival. Thus, based on a biomaterial approach, our current study provides new insight for 5‐NOT–containing hydrogels as a promising candidate to speed up recovery after central nervous system injuries.

Leaf extracts of eight selected southern African medicinal plants modulate pro-inflammatory cytokine secretion in LPS-stimulated RAW 264.7 macrophages

“…Similarly, 5-noniloxytryptamine (peak C; Fig. 9 ) is a potent neuroprotective agent (Saini et al 2016 ; Kalotra et al 2020 ; Kalotra and Kaur 2021 ). Notably, 5-noniloxytryptamine mimics polysialic acid (PSA), which is required for inducing and maintaining plasticity and repair of the nervous system upon tissue injury (Doğanyiğit and Üner 2021 ).…”

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

“…Although one can expect 10 to 100 times higher concentrations to show such effects in vivo, these concentrations could be acceptable pharmacologically and economically. Importantly, within the range of these doses, ursolic acid and 5-nonyloxytryptamine have improved functional recovery in injured mice [ 37 , 38 , 39 ], with the ursolic acid used by Sahu et al [ 36 ] to show its pro-active functions in spinal cord regeneration, being derived from the screen described in the present study. Importantly also, several HNK1 mimetics have been FDA approved for other types of indications.…”

“…5-Nonyloxytryptamine, a 5-HT1B serotonin receptor agonist [ 47 ], was identified to be a mimetic also for polysialic acid, which is predominantly attached to the neural cell adhesion molecule NCAM and essential not only for development but also for maintenance and repair of nervous system functions in the adult [ 48 , 49 ]. It improves recovery after injury of the central nervous system when injected into the cerebrospinal fluid or applied on collagen-laminin scaffolds [ 37 , 39 ]. It also contributes to synaptic activity and plasticity [ 49 ].…”

Importance of brain alterations in spinal cord injury

“…2 Subsequent biochemical events in secondary injury include vascular damage, ischemia, hypoxia, increased cell permeability, ionic deregulation, excitotoxicity, lipid peroxidation, free radical formation, apoptosis, inflammation, edema, demyelination, fibroglial scar, and cyst formation. 3,4 Great progress has been achieved in SCI treatments, including the transplantation of exogenous stem/progenitor cells, [5][6][7][8] olfactory ensheathing cells, [9][10][11] glial cell/Schwann cells, [12][13][14][15] and peripheral nerve grafts 16,17 ; the knockout of Chondroitin sulfate proteoglycans receptors [18][19][20] ; and the implantation of biomaterials [21][22][23][24][25][26][27] (Table 1). These experimental treatments promote the restoration of residual structure/function, the integration of replacement tissues, and the formation of new neurons/fibers in the damaged zone.…”