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

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.

Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair.

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.

Inhibition of the bacterial lectins of Pseudomonas aeruginosa with monosaccharides and peptides.

Pseudomonas aeruginosa (PA) can cause infections in compromised hosts by interacting with the glycocalyx of host epithelial cells. It binds to glycostructures on mucosal surfaces via two lectins, which are carbohydrate-binding proteins, named PA-IL and PA-IIL, and blocking this interaction is, thus, an attractive anti-adhesive strategy. The aim of this study was to determine by ciliary beat frequency (CBF) analysis whether monosaccharides or peptides mimicking glycostructures represent blockers of PA lectin binding to human airway cilia. The treatment with monosaccharides and peptides alone did not change the CBF compared to controls and the tested compounds did not influence the cell morphology or survival, with the exception of peptide pOM3. PA-IL caused a decrease of the CBF within 24 h. D-galactose as well as the peptides mimicking HNK-1, polysialic acid and fucose compensated the CBF-modulating effect of PA-IL with different affinities. PA-IIL also bound to the human airway cilia in cell culture and resulted in a decrease of the CBF within 24 h. L(-)-fucose and pHNK-1 blocked the CBF-decreasing effect of PA-IIL. The HNK-1-specific glycomimetic peptide had a high affinity for binding to both PA-IL and PA-IIL, and inhibited the ciliotoxic effect of both lectins, thus, making it a strong candidate for a therapeutic anti-adhesive drug.

Differential Induction of Lipoxygenase Isoforms in Wheat upon Treatment with Rust Fungus Elicitor, Chitin Oligosaccharides, Chitosan, and Methyl Jasmonate.

A glycopeptide elicitor prepared from germ tubes of the rust fungus Puccinia graminis Pers. f. sp. tritici Erikss. & Henn (Pgt), as well as chitin oligosaccharides, chitosan, and methyl jasmonate (MJ) stimulated lipoxygenase (LOX) activity (E.C. 1.13.11.12) in wheat (Triticum aestivum) leaves. Immunoblot analysis using anti-LOX antibodies revealed the induction of 92- and 103-kD LOX species after Pgt elicitor treatment. In contrast, MJ treatment led to a significant increase of a 100-kD LOX species, which was also detected at lower levels in control plants. The effects of chitin oligomers and chitosan resembled those caused by MJ. In conjunction with other observations the results suggest that separate reaction cascades exist, and that jasmonates may not be involved in Pgt elicitor action. LOX-92 appears to be mainly responsible for the increase in LOX activity after Pgt elicitor treatment because its appearance on western blots coincided with high LOX activity in distinct anion-exchange chromatography fractions. It is most active at pH 5.5 to 6.0, and product formation from linoleic and [alpha]-linolenic acid is clearly in favor of the 9-LOOHs. It is interesting that a 92-kD LOX species, which seems to correspond to the Pgt elicitor-induced LOX species, was also detected in rust-inoculated leaves.