Askari Hamid, Yavarpour-Bali Hanie, Shirzad Moein, Sadeghi Farzin, Biagini Giuseppe, Ghasemi-Kasman Maryam
Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
Eur J Pharmacol. 2025 Sep 5;1002:177851. doi: 10.1016/j.ejphar.2025.177851. Epub 2025 Jun 17.
Multiple sclerosis (MS), a chronic neuroinflammatory disorder, involves demyelination and neurodegeneration, necessitating therapies that currently target inflammation and enhance myelin repair. This study investigated the combined efficacy of mesenchymal stem cell (MSC)-derived exosomes (EXOs) and MCC950, a NLRP3 inflammasome inhibitor, in a cuprizone (CPZ)-induced demyelination mouse model. Thirty male C57BL/6J mice were assigned to five groups: healthy control, CPZ + Saline, CPZ + EXOs, CPZ + MCC950, and CPZ + EXOs + MCC950. Exosomes were isolated from rat bone marrow MSCs, characterized, and confirmed to localize to the brain via Dil staining. Over six weeks, CPZ-induced corpus callosum demyelination was followed by two weeks of treatment. Behavioral assessments (Y-maze), histopathology (FluoroMyelin, PLP/GFAP immunofluorescence), oxidative stress marker (MDA, TAC, SOD/CAT/GPx), and qRT‒PCR analyses of oligodendrocyte lineage, inflammatory, and antioxidant genes were performed. Behavioral improvements in spatial memory were comparable across treatments. Compared with monotherapy, combined EXOs-MCC950 therapy increased remyelination, as evidenced by elevated oligodendrocyte lineage markers (PDGFRα, Olig2, and MBP), reduced the extent of demyelination, and restored PLP expression. Neuroinflammation was suppressed via reduced astrocytes and proinflammatory cytokines expression (IL-1β, IL-18, and TNF-α). EXOs treatment upregulated Nrf2-driven antioxidant genes (HO-1, NQO1, and Nrf2), whereas MCC950 restored antioxidant enzyme activity (MDA/TAC/CAT/SOD/GPx). These findings demonstrate that combining EXOs with MCC950 improves myelin repair via attenuating inflammation and oxidative stress.
多发性硬化症（MS）是一种慢性神经炎症性疾病，涉及脱髓鞘和神经变性，需要目前针对炎症并促进髓鞘修复的治疗方法。本研究在铜螯合剂（CPZ）诱导的脱髓鞘小鼠模型中，研究了间充质干细胞（MSC）衍生的外泌体（EXOs）与NLRP3炎性小体抑制剂MCC950的联合疗效。将30只雄性C57BL/6J小鼠分为五组：健康对照、CPZ + 生理盐水、CPZ + EXOs、CPZ + MCC950以及CPZ + EXOs + MCC950。从大鼠骨髓间充质干细胞中分离出外泌体，进行表征，并通过Dil染色确认其在脑内的定位。在六周内，CPZ诱导胼胝体脱髓鞘，随后进行两周的治疗。进行行为评估（Y迷宫）、组织病理学（FluoroMyelin、PLP/GFAP免疫荧光）分析、氧化应激标志物（MDA、TAC、SOD/CAT/GPx）以及少突胶质细胞谱系、炎症和抗氧化基因的qRT-PCR分析。各治疗组在空间记忆方面的行为改善相当。与单一疗法相比，EXOs-MCC950联合疗法增加了髓鞘再生，表现为少突胶质细胞谱系标志物（PDGFRα、Olig2和MBP）升高，脱髓鞘程度降低，PLP表达恢复。通过减少星形胶质细胞和促炎细胞因子表达（IL-1β、IL-18和TNF-α）抑制神经炎症。EXOs治疗上调了Nrf2驱动的抗氧化基因（HO-1、NQO1和Nrf2），而MCC950恢复了抗氧化酶活性（MDA/TAC/CAT/SOD/GPx）。这些发现表明，将EXOs与MCC950联合使用可通过减轻炎症和氧化应激来改善髓鞘修复。
