Protective role of mirtazapine in adult female Mecp2(+/-) mice and patients with Rett syndrome.
Protective role of mirtazapine in adult female Mecp2(+/-) mice and patients with Rett syndrome.
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DOI：
10.1186/s11689-020-09328-z
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发表时间：
2020-09-28
影响因子：
4.9
通讯作者：
Tongiorgi E
中科院分区：
文献类型：
--
作者：
Flores Gutiérrez J;De Felice C;Natali G;Leoncini S;Signorini C;Hayek J;Tongiorgi E
Rett综合征（RTT）是一种X连锁的神经发育罕见疾病，主要由MECP 2基因突变引起，是一种典型的智力残疾障碍。在缺乏Mecp 2基因的成年小鼠模型中，RTT样表型的可逆性为治疗任何年龄的疾病带来了希望。然而，成人RTT患者仍然迫切需要新的治疗方法。鉴于RTT和单胺缺乏症之间的关系，我们研究了米氮平（MTZ），一种去甲肾上腺素能和特异性肾上腺素能抗抑郁药，作为一种潜在的治疗。用10 mg/kg MTZ处理成年异源Mecp 2（HET）雌性小鼠（6个月大）30天，并评估一般健康状况、运动技能、运动学习和焦虑。分析运动皮层、躯体感觉皮层和杏仁核的小白蛋白表达。80例携带致病性MECP 2突变的RTT成年女性患者被随机分配接受MTZ治疗失眠和情绪障碍（平均年龄= 23.1 ± 7.5岁，范围= 16-47岁;平均MTZ治疗持续时间= 1.64 ± 1.0年，范围= 0.08-5.0年）。采用Rett临床严重程度量表（RCSS）和运动行为评定量表（MBAS）进行回顾性分析。在HET小鼠中，MTZ使运动学习免于恶化，并使初级运动皮层中的小清蛋白水平正常化。此外，MTZ挽救了HET小鼠在高架十字迷宫（高架十字迷宫）中观察到的异常开放臂偏好行为，并使桶状皮质中的小白蛋白表达正常化。由于胡须修剪也取消了EPM相关的表型，我们建议这是由于感觉超敏反应。在患者中，MTZ减缓了疾病进展或诱导了M1社会行为区域的10/16项MBAS项目的显著改善：M2口面/呼吸区域的4/7项和M3运动/体征区域的8/14项。这项研究提供了第一个证据，证明成年雌性杂合子Mecp2tm1.1Bird小鼠和成年Rett患者对抗抑郁药米氮平的长期治疗耐受性良好，并且可以防止疾病进展并改善运动，感觉和行为症状。
Rett syndrome (RTT), an X-linked neurodevelopmental rare disease mainly caused by MECP2-gene mutations, is a prototypic intellectual disability disorder. Reversibility of RTT-like phenotypes in an adult mouse model lacking the Mecp2-gene has given hope of treating the disease at any age. However, adult RTT patients still urge for new treatments. Given the relationship between RTT and monoamine deficiency, we investigated mirtazapine (MTZ), a noradrenergic and specific-serotonergic antidepressant, as a potential treatment. Adult heterozygous-Mecp2 (HET) female mice (6-months old) were treated for 30 days with 10 mg/kg MTZ and assessed for general health, motor skills, motor learning, and anxiety. Motor cortex, somatosensory cortex, and amygdala were analyzed for parvalbumin expression. Eighty RTT adult female patients harboring a pathogenic MECP2 mutation were randomly assigned to treatment to MTZ for insomnia and mood disorders (mean age = 23.1 ± 7.5 years, range = 16–47 years; mean MTZ-treatment duration = 1.64 ± 1.0 years, range = 0.08–5.0 years). Rett clinical severity scale (RCSS) and motor behavior assessment scale (MBAS) were retrospectively analyzed. In HET mice, MTZ preserved motor learning from deterioration and normalized parvalbumin levels in the primary motor cortex. Moreover, MTZ rescued the aberrant open-arm preference behavior observed in HET mice in the elevated plus-maze (EPM) and normalized parvalbumin expression in the barrel cortex. Since whisker clipping also abolished the EPM-related phenotype, we propose it is due to sensory hypersensitivity. In patients, MTZ slowed disease progression or induced significant improvements for 10/16 MBAS-items of the M1 social behavior area: 4/7 items of the M2 oro-facial/respiratory area and 8/14 items of the M3 motor/physical signs area. This study provides the first evidence that long-term treatment of adult female heterozygous Mecp2tm1.1Bird mice and adult Rett patients with the antidepressant mirtazapine is well tolerated and that it protects from disease progression and improves motor, sensory, and behavioral symptoms.
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影响因子：
2
作者：
Downs, Jenny;Geranton, Sandrine M.;Bebbington, Ami;Jacoby, Peter;Bahi-Buisson, Nadia;Ravine, David;Leonard, Helen
通讯作者：
Leonard, Helen
影响因子：
4.9
作者：
Barnes, Katherine V.;Coughlin, Francesca R.;Kaufmann, Walter E.
通讯作者：
Kaufmann, Walter E.
影响因子：
5.7
作者：
Connolly, Daniel R.;Zhou, Zhaolan
通讯作者：
Zhou, Zhaolan
影响因子：
1.9
作者：
Erlandson, A;Hagberg, B
通讯作者：
Hagberg, B
影响因子：
4
作者：
Cuddapah VA;Pillai RB;Shekar KV;Lane JB;Motil KJ;Skinner SA;Tarquinio DC;Glaze DG;McGwin G;Kaufmann WE;Percy AK;Neul JL;Olsen ML
通讯作者：
Olsen ML