State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shanghai Green Valley Pharmaceutical Co., Ltd, Shanghai, China.
CNS Neurosci Ther. 2024 Jul;30(7):e14847. doi: 10.1111/cns.14847.
Growing evidence suggests that an imbalanced gut microbiota composition plays a crucial role in the development of neuromyelitis optica spectrum disorders (NMOSD), an inflammatory demyelinating disease primarily affecting the optic nerves and central nervous system (CNS). In light of this, we explored the potential therapeutic benefits of GV-971 in NMOSD. GV-971 is a drug used for treating mild-to-moderate Alzheimer's disease, which targets the gut-brain axis and reduces neuroinflammation.
To evaluate GV-971's effects, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model to establish NMOSD animal models. This was achieved by injecting NMO-IgG into aged mice (11 months old) or using NMO-IgG along with complement injection and microbubble-enhanced low-frequency ultrasound (MELFUS) techniques in young mice (7 weeks old). We assessed the impact of GV-971 on incidence rate, clinical scores, body weight, and survival, with methylprednisolone serving as a positive control. In NMOSD models of young mice, we analyzed spinal cord samples through H&E staining, immunohistochemistry, and Luxol Fast Blue staining. Fecal samples collected at different time points underwent 16S rRNA gene sequencing, while plasma samples were analyzed using cytokine array and untargeted metabolomics analysis.
Our findings indicated that GV-971 significantly reduced the incidence of NMOSD, alleviated symptoms, and prolonged survival in NMOSD mouse models. The NMOSD model exhibited substantial neuroinflammation and injury, accompanied by imbalances in gut microbiota, peripheral inflammation, and metabolic disorders, suggesting a potentially vicious cycle that accelerates disease pathogenesis. Notably, GV-971 effectively reduces neuroinflammation and injury, and restores gut microbiota composition, as well as ameliorates peripheral inflammation and metabolic disorders.
GV-971 attenuates the progression of NMOSD in murine models and reduces neuroinflammation and injury, likely through its effects on remodeling gut microbiota and peripheral inflammation and metabolic disorders.
越来越多的证据表明，肠道微生物群落组成失衡在视神经脊髓炎谱系疾病（NMOSD）的发展中起着关键作用，NMOSD 是一种主要影响视神经和中枢神经系统（CNS）的炎症性脱髓鞘疾病。有鉴于此，我们探讨了 GV-971 在 NMOSD 中的潜在治疗益处。GV-971 是一种用于治疗轻度至中度阿尔茨海默病的药物，其作用靶点是肠脑轴，可减轻神经炎症。
为了评估 GV-971 的作用，我们使用实验性自身免疫性脑脊髓炎（EAE）小鼠模型来建立 NMOSD 动物模型。该模型通过向老年小鼠（11 个月大）注射 NMO-IgG 或在年轻小鼠（7 周龄）中使用 NMO-IgG 联合补体注射和微泡增强低频超声（MELFUS）技术来建立。我们评估了 GV-971 对发病率、临床评分、体重和存活率的影响，以甲基强的松龙作为阳性对照。在年轻小鼠的 NMOSD 模型中，我们通过 H&E 染色、免疫组织化学和卢索快速蓝染色分析脊髓样本。在不同时间点收集的粪便样本进行 16S rRNA 基因测序，而血浆样本则进行细胞因子阵列和非靶向代谢组学分析。
我们的研究结果表明，GV-971 显著降低了 NMOSD 的发病率，缓解了 NMOSD 小鼠模型的症状，并延长了其生存时间。NMOSD 模型表现出明显的神经炎症和损伤，同时伴有肠道微生物群落失衡、外周炎症和代谢紊乱，这表明一个潜在的恶性循环加速了疾病的发病机制。值得注意的是，GV-971 可有效减轻神经炎症和损伤，并恢复肠道微生物群落组成，同时改善外周炎症和代谢紊乱。
GV-971 可减缓 NMOSD 小鼠模型的进展，并减轻神经炎症和损伤，可能是通过重塑肠道微生物群落和外周炎症及代谢紊乱来实现的。
