Lin Ching-Yi, Li Kevin, Gitchell Thomas, Lee Yu-Shang
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Int J Mol Sci. 2024 Dec 30;26(1):239. doi: 10.3390/ijms26010239.
Spinal cord injury (SCI) results in functional deficits below the injured spinal level. The descending serotonergic system in the spinal cord is critically involved in the control of motor and autonomic functions. Specifically, SCI damages the projections of serotonergic fibers, which leads to reduced serotonin inputs and increased amounts of spinal serotonergic receptors. Our previous pharmacological study demonstrated that brief administration of a highly selective 5-HT receptor agonist, NLX-112, improves lower urinary tract (LUT) function at the termination stage of thoracic 8 (T8) contusive SCI in rats. However, whether chronic activation of serotonin 5-HT receptors by NLX-112 after SCI is beneficial remains an unanswered question. Here, we evaluated the efficacy of long-term NLX-112 intervention starting from two weeks post-T8 contusive SCI for an additional six weeks. We evaluated locomotion, LUT function, bladder morphology, and the number of spinal 5-HT receptors in both L4 and L6/S1 spinal cord segments. Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT receptors to treat SCI.
脊髓损伤（SCI）会导致损伤脊髓节段以下出现功能缺陷。脊髓中的下行5-羟色胺能系统在运动和自主功能控制中起关键作用。具体而言，SCI会损害5-羟色胺能纤维的投射，导致5-羟色胺输入减少以及脊髓5-羟色胺能受体数量增加。我们之前的药理学研究表明，在大鼠胸8（T8）挫伤性SCI的终末期，短暂给予高选择性5-羟色胺受体激动剂NLX-112可改善下尿路（LUT）功能。然而，SCI后NLX-112对5-羟色胺5-HT受体的慢性激活是否有益仍是一个未解决的问题。在此，我们评估了从T8挫伤性SCI后两周开始进行为期六周的长期NLX-112干预的疗效。我们评估了L4和L6/S1脊髓节段的运动功能、LUT功能、膀胱形态以及脊髓5-HT受体数量。我们的结果表明，与接受载体处理的SCI动物相比，NLX-112治疗以剂量依赖的方式显著改善运动功能，改善LUT功能，减轻膀胱重量和膀胱壁厚度，并减少SCI上调的脊髓5-HT受体。这些数据表明，长期激活5-HT受体的NLX-112在治疗SCI方面具有可观的治疗潜力。
