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Abstract：
Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target \"BDNF\" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.
摘要：
Rett综合征（RTT）是一种无法治愈的进行性X连锁神经发育障碍。RTT患者在18月龄内表现出疾病相关症状，包括发育退化，逐渐失去有用的手部动作，呼吸困难,伴随着神经损伤，癫痫发作,震颤,和精神残疾。Rett综合征也与代谢异常有关,抗糖尿病药物二甲双胍被认为是一种潜在的选择药物，副作用低或无副作用。以前,我们发现二甲双胍在人脑细胞系中的体外暴露诱导MECP2E1转录本，大脑中MECP2基因的显性同工型，导致RTT的突变。这里,我们报道了二甲双胍对小鼠的分子影响。通过免疫印迹对雄性和雌性小鼠的特定脑区进行蛋白质分析，表明二甲双胍在海马中诱导MeCP2，以性别依赖的方式。其他实验证实，二甲双胍对MeCP2靶标“BDNF”的调节作用是大脑区域依赖性和性别特异性的。核糖体蛋白S6（磷酸化和非磷酸化形式）的测量证实了二甲双胍在肝脏中的性别依赖性作用。我们的结果可以帮助更好地理解二甲双胍在雄性和雌性成年小鼠不同脑区的分子影响。同时为其在Rett综合征治疗策略中的潜力提供了一些见解。
