Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios
Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios
复制标题
布美他尼给药后自闭症谱系障碍儿童的症状改善与 GABA/谷氨酸比率降低有关
DOI：
10.1038/s41398-020-0692-2
复制
发表时间：
2020-01-27
影响因子：
6.8
通讯作者：
Li, Fei
中科院分区：
文献类型：
--
作者：
Zhang, Lingli;Huang, Chu-Chung;Li, Fei
据报道，布美他尼通过增强γ -氨基丁酸（GABA）的作用来改变突触兴奋-抑制（E-I）平衡，从而减轻动物模型中自闭症谱系障碍（ASD）的严重程度。然而，其对年轻ASD患者疗效的临床证据有限。目前的临床试验对83名患者进行了调查，随机分为布美他尼组（布美他尼治疗，0.5mg，每日两次）或对照组（不布美他尼治疗）。初级[儿童自闭症评定量表（CARS）]、次级[临床总体印象（CGI）]和探索性[抑制性（γ -氨基丁酸，GABA）和兴奋性（谷氨酸，Glx）神经递质浓度通过磁共振波谱（MRS）测量岛叶皮层（IC）和视觉皮层（VC）]结果测量在基线和3个月的随访中进行评估。在整个治疗过程中监测副作用。与对照组相比，布美他尼组症状严重程度显著降低，这可以从CARS总评分和>= 3评分项目数中看出。临床症状的改善经CGI证实。在3个月的时间里，布美他尼组IC和VC中GABA/Glx比值比对照组下降得更快。这种IC的降低与布美他尼组的症状改善有关。我们的研究证实了布美他尼在缓解幼儿ASD核心症状方面的临床疗效，这是第一次证明这种改善与GABA/Glx比值的降低有关。本研究提示MRS测量的GABA/Glx比值可作为评价布美他尼治疗效果的神经影像学生物标志物。
Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of gamma-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score >= 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.