加州大学M. H. Tuszynski课题组近日取得一项新成果。经过不懈努力，他们发现了Thiorphan重编程神经元以促进脊髓损伤后的功能恢复。相关论文于2025年10月29日发表于国际顶尖学术期刊《自然》杂志上。

研究小组之前发现脊髓损伤后皮质脊髓运动神经元转录组的胚胎转移与成功的轴突再生有关。利用这种转录再生的“特征”，研究人员使用计算机模拟筛选技术来鉴定在转录组中产生类似变化的小分子，并将硫脲素（一种中性内肽酶抑制剂）确定为主要候选者。在一项新的成人运动皮质神经元体外筛选中，硫脲素使神经突生长增加1.8倍（P <0.001）。随后在严重C5脊髓挫伤模型中进行中枢神经系统持续给药（伤后2周开始），当联合神经干细胞移植时，硫脲素显著改善前肢运动功能（P < 0.005）并促进皮质脊髓再生（P < 0.05）。为验证临床转化价值，我们在56岁人类捐赠者的原代皮层神经元培养中发现硫脲素同样显著促进神经突生长。这项研究开创了从计算机模拟筛选到成人脑组织验证的新药研发路径。

附：英文原文

Title: Thiorphan reprograms neurons to promote functional recovery after spinal cord injury

Author: van Niekerk, E. A., de Freria, C. Marques, Mancarci, B. O., Groeniger, K., Kulinich, D., Riley, T., Kawaguchi, R., Okawa, S., Vokes, T., Rosenzweig, E. S., Sinopoulou, E., Castle, M. J., Huie, R., Ferguson, A. R., Kfoury-Beaumont, N., Khalessi, A., Pavlidis, P., Tuszynski, M. H.

Issue&Volume: 2025-10-29

Abstract: We previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration1. Exploiting this transcriptional regenerative ‘signature’, here we used in silico screens to identify small molecules that generate similar shifts in the transcriptome, and identified thiorphan—a neutral endopeptidase inhibitor—as a lead candidate. In a new adult motor cortex neuronal in vitro screen2, thiorphan increased neurite outgrowth 1.8-fold (P<0.001). We then infused thiorphan into the central nervous system beginning 2weeks after severe C5 spinal cord contusions and, when combined with a neural stem cell graft, thiorphan elicited significant improvements in forelimb function (P<0.005) and corticospinal regeneration (P<0.05). Extending clinical relevance, thiorphan significantly increased neurite outgrowth in primary cortical neuronal cultures from a 56-year-old human. These findings represent a new path for drug discovery, starting from in silico screens to proof-of-concept in adult human brain cultures.

DOI: 10.1038/s41586-025-09647-y

Source: https://www.nature.com/articles/s41586-025-09647-y