Landzhov Boycho, Gaydarski Lyubomir, Stanchev Stancho, Kostadinova Ivanka, Iliev Alexandar, Kotov Georgi, Rashev Pavel, Mourdjeva Milena, Pupaki Despina, Stamenov Nikola
Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria.
Department of Pharmacology, Pharmacotherapy and Toxicology, Medical University of Sofia, 1000 Sofia, Bulgaria.
Int J Mol Sci. 2024 Dec 3;25(23):13011. doi: 10.3390/ijms252313011.
Multiple sclerosis (MS) is a chronic neurodegenerative disorder involving demyelination. The cuprizone model is commonly used to study MS by inducing oligodendrocyte stress and demyelination. The subventricular zone (SVZ) plays a key role in neurogenesis, while the neuronal/glial antigen 2 (NG2) is a marker for immature glial cells, involved in oligodendrocyte differentiation. The apelin receptor (APLNR) is linked to neurogenesis and behavior modulation. This study explores the role of APLNR in NG2-positive cells during de- and remyelination phases in the experimental cuprizone mouse model. Thirty male C57BL/6 mice were divided into control (not treated), demyelination (5 weeks cuprizone administration), and remyelination (5 weeks cuprizone administration + 5 weeks recovery) groups. Histological examinations, immunohistochemistry, and immunofluorescence on serial coronal sections were conducted to evaluate corpus callosum (CC) morphology and APLNR and NG2 expression in the SVZ, in addition to behavioral assessments. The histological analysis showed a significant reduction in the CC's thickness and area after five weeks of cuprizone exposure, followed by recovery five weeks post-exposure. During the demyelination phase, APLNR-expressing cells peaked while NG2-positive cells decreased. In the remyelination phase, APLNR-expressing cells declined, and NG2-positive cells increased. Confocal microscopy confirmed the co-localization of NG2 and APLNR markers. Statistically significant differences were observed across experimental groups. Correlation analyses highlighted associations between APLNR/NG2 cell counts and CC changes. Behavioral tests revealed impaired motor coordination and memory during demyelination, with gradual recovery during remyelination. Significant changes in the CC structure and the number of APLNR and NG2-positive cells were observed during de- and remyelination, suggesting that NG2-positive cells expressing APLNR may play a key role in remyelination.
多发性硬化症（MS）是一种涉及脱髓鞘的慢性神经退行性疾病。铜螯合剂模型常用于通过诱导少突胶质细胞应激和脱髓鞘来研究MS。脑室下区（SVZ）在神经发生中起关键作用，而神经元/胶质抗原2（NG2）是未成熟胶质细胞的标志物，参与少突胶质细胞的分化。阿片肽受体（APLNR）与神经发生和行为调节有关。本研究在实验性铜螯合剂小鼠模型中，探讨了APLNR在脱髓鞘和髓鞘再生阶段NG2阳性细胞中的作用。将30只雄性C57BL/6小鼠分为对照组（未处理）、脱髓鞘组（给予5周铜螯合剂）和髓鞘再生组（给予5周铜螯合剂+5周恢复期）。除行为评估外，还对连续冠状切片进行了组织学检查、免疫组织化学和免疫荧光分析，以评估胼胝体（CC）形态以及SVZ中APLNR和NG2的表达。组织学分析显示，铜螯合剂暴露5周后，CC的厚度和面积显著减小，暴露后5周恢复。在脱髓鞘阶段，表达APLNR的细胞达到峰值，而NG2阳性细胞减少。在髓鞘再生阶段，表达APLNR的细胞减少，NG2阳性细胞增加。共聚焦显微镜证实了NG2和APLNR标志物的共定位。各实验组之间观察到统计学上的显著差异。相关性分析突出了APLNR/NG2细胞计数与CC变化之间的关联。行为测试显示，脱髓鞘期间运动协调和记忆受损，髓鞘再生期间逐渐恢复。在脱髓鞘和髓鞘再生期间，观察到CC结构以及APLNR和NG2阳性细胞数量的显著变化，这表明表达APLNR的NG2阳性细胞可能在髓鞘再生中起关键作用。
