Bushman J, Mishra B, Ezra M, Gul S, Schulze C, Chaudhury S, Ripoll D, Wallqvist A, Kohn J, Schachner M, Loers G
New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA.
Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
Neuropharmacology. 2014 Apr;79:456-66. doi: 10.1016/j.neuropharm.2013.09.014. Epub 2013 Sep 22.
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.
通过蛋白质或脂质附着于细胞表面或暴露于细胞外基质中的聚糖会影响许多细胞过程，包括神经突生长、细胞存活和迁移，以及突触活动和可塑性。这些功能使聚糖成为刺激受损神经系统修复的有吸引力的分子。然而，聚糖通常难以合成或分离，并且在复杂的组织环境中具有不稳定的缺点。为了规避这些问题，我们筛选了一个有机小分子化合物库，以寻找神经刺激聚糖聚唾液酸（PSA）的结构和功能模拟物，并确定5-HT4受体激动剂替加色罗为PSA模拟物。替加色罗的PSA模拟活性在小鼠中枢和外周神经系统细胞培养中得到证实，并且发现其与作为血清素（5-HT4）受体激动剂的既定功能无关。在一个外周神经再生的体内模型中，与接受载体对照的对照小鼠相比，在损伤部位接受替加色罗的小鼠显示出功能测量和组织学证据表明的恢复增强。这些数据表明，替加色罗可重新用于治疗神经系统损伤，并强调了使用小分子作为神经刺激聚糖模拟物的潜力。
