Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Neurochem. 2024 May;168(5):841-854. doi: 10.1111/jnc.15960. Epub 2023 Sep 30.
Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.
雷特综合征是一种 X 连锁神经发育障碍，由 Mecp2 基因突变引起，主要影响女性。神经胶质细胞功能障碍与 Rett 综合征（RTT）患者和该疾病的小鼠模型中的神经胶质细胞功能障碍有关，可影响突触发生、神经胶质代谢和炎症。在这里，我们评估了用树枝状聚合物连接的 N-乙酰半胱氨酸（D-NAC）治疗成年（5-6 个月大）有症状的 Mecp2 杂合雌性小鼠是否会改善行为表型、睡眠和神经胶质炎症特征。我们发现，对成年 Mecp2 杂合小鼠海马体和纹状体进行无偏全代谢组学分析表明，与神经炎症相关的脂质代谢存在显著差异，为该模型中靶向神经胶质炎症提供了依据。我们的结果表明，每周一次用 D-NAC（10mg/kg NAC）治疗比等效剂量的游离 NAC 更能有效改善有症状的 Mecp2 杂合雌性小鼠的大体神经行为表型。我们还表明，D-NAC 治疗在改善异常表型的几个方面明显优于生理盐水，包括爪子紧握、运动、恐惧记忆、快速眼动睡眠和癫痫样活动负担。与生理盐水处理的 Mecp2 杂合子小鼠相比，全身性 D-NAC 治疗可显著改善小胶质细胞促炎细胞因子的产生，并可改善爪子紧握、运动、恐惧记忆和快速眼动睡眠以及癫痫样活动负担等多个表型特征。与生理盐水处理的 Mecp2 杂合子小鼠相比，在症状出现后对年龄较大的临床相关雷特综合征模型进行系统性神经胶质靶向 D-NAC 治疗显示出改善神经行为损伤以及睡眠模式和癫痫样活动负担的潜力。这些发现为该方法治疗雷特综合征患者的转化价值提供了依据。
