Shao Yu, Liu Yan-Bo, Yu Dong-Kun, Yang Zhi-Lun, Feng Zi-Qi, Mi Xiao-Juan, Liu Juan
School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
Curr Med Sci. 2025 Jul 11. doi: 10.1007/s11596-025-00078-4.
Schizophrenia is a complex neuropsychiatric disorder characterized by cognitive, affective, and behavioral abnormalities. Existing treatments have yielded limited effects on improving cognitive function. Recent studies have identified the abnormal differentiation of hippocampal neural stem cells (NSCs), neuronal loss, and dysregulated proliferation of astrocytes as significant pathological mechanisms contributing to the symptoms of schizophrenia. Impaired hippocampal neurogenesis may lead to emotional and cognitive deficits and biases in learning and memory, indicating that NSC differentiation is critical. NEP1-40, a Nogo-A receptor inhibitor, has shown promise for nerve protection and repair promotion. However, the effects of NEP1-40 on stem cell differentiation, the reduction in neuronal apoptosis, and the amelioration of schizophrenia-like behaviors have not been adequately investigated. This study examined the influence of NEP1-40 on NSC differentiation, hippocampal neuronal apoptosis, and proliferation in adolescent mice, along with its potential to enhance cognitive and behavioral outcomes in MK-801-induced schizophrenia mouse models.
In in vivo experiments, a schizophrenia mouse model was successfully established. Subsequently, behavioral tests were conducted, followed by Western blotting (WB) and immunofluorescence (IF) analyses. In in vitro settings, NSCs were cultured and transfected. Flow cytometry, along with WB and IF assays, was employed to evaluate the effects of NEP1-40.
Schizophrenia-like behaviors in mice were significantly improved with the overexpression of NEP1-40. Compared with the model group, the NEP1-40 treatment group presented increased expression of a neuronal marker (Tuj1), reduced expression of an astroglial marker (GFAP), and decreased hippocampal neuronal apoptosis. NSC differentiation was assessed by quantifying the number of BrdU-positive cells coexpressing Tuj1 and GFAP in the hippocampal dentate gyrus. NEP1-40 treatment led to an increase in BrdU/Tuj1-positive cells and a reduction in BrdU/GFAP-positive cells. In cellular studies, NEP1-40 overexpression similarly increased the number of Tuj1-positive cells, reduced the number of GFAP-positive cells, decreased the degree of neuronal apoptosis, and promoted neuronal proliferation.
These findings demonstrated the neurogenic effects of NEP1-40 on NSCs and their potential to mitigate schizophrenia-like behaviors in vivo.
精神分裂症是一种复杂的神经精神疾病，其特征为认知、情感和行为异常。现有治疗方法在改善认知功能方面效果有限。最近的研究已确定海马神经干细胞（NSC）异常分化、神经元丢失以及星形胶质细胞增殖失调是导致精神分裂症症状的重要病理机制。海马神经发生受损可能导致情绪和认知缺陷以及学习和记忆偏差，这表明NSC分化至关重要。NEP1-40是一种Nogo-A受体抑制剂，已显示出神经保护和促进修复的潜力。然而，NEP1-40对干细胞分化、神经元凋亡减少以及精神分裂症样行为改善的影响尚未得到充分研究。本研究考察了NEP1-40对青春期小鼠NSC分化、海马神经元凋亡和增殖的影响，以及其增强MK-801诱导的精神分裂症小鼠模型认知和行为结果的潜力。
在体内实验中，成功建立了精神分裂症小鼠模型。随后进行行为测试，接着进行蛋白质免疫印迹（WB）和免疫荧光（IF）分析。在体外实验中，培养并转染NSC。采用流式细胞术以及WB和IF检测来评估NEP1-40的作用。
NEP1-40过表达显著改善了小鼠的精神分裂症样行为。与模型组相比，NEP1-40治疗组神经元标志物（Tuj1）表达增加，星形胶质细胞标志物（GFAP）表达降低，海马神经元凋亡减少。通过量化海马齿状回中同时表达Tuj1和GFAP的BrdU阳性细胞数量来评估NSC分化。NEP1-40治疗导致BrdU/Tuj1阳性细胞增加，BrdU/GFAP阳性细胞减少。在细胞研究中，NEP1-40过表达同样增加了Tuj1阳性细胞数量，减少了GFAP阳性细胞数量，降低了神经元凋亡程度，并促进了神经元增殖。
这些发现证明了NEP1-40对NSC的神经发生作用及其在体内减轻精神分裂症样行为的潜力。
