Dragoni Francesca, Garau Jessica, Rizzo Bartolo, Orcesi Simona, Varesio Costanza, Di Gerlando Rosalinda, Bordoni Matteo, Scarian Eveljn, Cereda Cristina, Pansarasa Orietta, Gagliardi Stella
IRCCS Mondino Foundation, 27100 Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy.
Genes (Basel). 2025 Jul 30;16(8):922. doi: 10.3390/genes16080922.
Aicardi-Goutières Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial abnormalities and increased reactive oxygen species (ROS) levels in lymphoblastoid cell lines (LCLs) derived from - and -mutated AGS patients. On this background, we turned our attention to metformin, the first-choice drug for type 2 diabetes, as a possible treatment acting on oxidative stress in RNASEH2-mutant AGS cells.
By means of flow cytometry, we found that metformin treatment significantly decreases ROS production in - and -mutated AGS LCLs. Of note, metformin treatment reduces the green JC-1 monomeric signal and, concurrently, increases the red JC-1 signal in both mutated LCLs, accounting for restoration of the mitochondrial membrane potential. Immunofluorescence staining shows a decrease in 8-oxoG levels only in - mutated AGS LCLs. Finally, the significant upregulation of Forkhead Box O3 (), cytochrome C somatic (), and superoxide dismutase 2 () mRNA levels in -mutated AGS LCLs after metformin treatment points to signaling as a possible mechanism to reduce oxidative stress.
In conclusion, even if these pilot results need to be confirmed on a larger cohort, we shed light on metformin treatment as a valid approach to ameliorate oxidative stress-related inflammation in AGS patients.
艾卡迪 - 古铁雷斯综合征（AGS）是一种罕见的神经炎症性疾病，其特征为早期出现的症状超出神经系统范围。由于该疾病罕见，其发病机制尚未完全明确，诊断和治疗仍具有挑战性。我们最近在源自携带 - 和 - 突变的AGS患者的淋巴母细胞系（LCLs）中证实了线粒体异常和活性氧（ROS）水平升高。在此背景下，我们将注意力转向二甲双胍，这是2型糖尿病的首选药物，作为一种可能作用于RNASEH2突变的AGS细胞氧化应激的治疗方法。
通过流式细胞术，我们发现二甲双胍治疗可显著降低携带 - 和 - 突变的AGS LCLs中的ROS生成。值得注意的是，二甲双胍治疗降低了两个突变LCLs中的绿色JC - 1单体信号，同时增加了红色JC - 1信号，这表明线粒体膜电位得以恢复。免疫荧光染色显示仅在携带 - 突变的AGS LCLs中8 - 氧代鸟嘌呤（8 - oxoG）水平降低。最后，二甲双胍治疗后携带 - 突变的AGS LCLs中叉头框O3（）、细胞色素C体（）和超氧化物歧化酶2（）mRNA水平的显著上调表明 信号传导可能是减轻氧化应激的一种机制。
总之，即使这些初步结果需要在更大的队列中得到证实，我们揭示了二甲双胍治疗作为改善AGS患者氧化应激相关炎症的有效方法。
