Sevoflurane ameliorates schizophrenia in a mouse model and patients: pre-clinical and clinical feasibility study
Sevoflurane ameliorates schizophrenia in a mouse model and patients: pre-clinical and clinical feasibility study
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七氟烷改善小鼠模型和患者的精神分裂症：临床前和临床可行性研究
DOI：
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发表时间：
2022
影响因子：
5.3
通讯作者：
Xingrong Song
中科院分区：
文献类型：
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作者：
Tianyun Zhao;Ziwen Shi;Nongxi Ling;Jingwen Qin;Quancai Zhou;Lingzhi Wu;Yuansheng Wang;Chuansong Lin;Daqing Ma;Xingrong Song
GABA能缺陷被认为与精神分裂症的病理生理有关，因此GABA受体A亚型(GABAARs)调节剂，如常用的挥发性麻醉剂七氟醚，可能对精神分裂症有治疗价值。本研究观察了低浓度七氟醚对MK801诱导的精神分裂样小鼠和精神分裂症患者的治疗作用。每天两次，共5天)，小鼠暴露于1%七氟醚1小时/天，连续5天。暴露后1周进行行为学检查、免疫组织化学分析、免疫印迹分析和电生理检查。10例精神分裂症患者给予1%七氟醚5h/d，疗程6d，分别于第1周和第2周进行阳性和阴性症状量表(PANSS)和18项简明精神病评定量表(BPRS-18)评定，MK801诱导的运动障碍和社会功能障碍，NMDARs亚单位和突触后密度蛋白95(PSD95)表达下调，小白蛋白和GAD67阳性神经元减少，mEPSCs和mIPSCs的幅度和频率改变，兴奋/抑制比增加。七氟醚可减弱MK-801引起的上述改变。6名患者和8名患者在治疗后1周和2周获得了PANSS总分至少减少30%的反应。治疗后第2周BPRS-18总分下降38%(p<；0.01)。低浓度七氟醚能有效逆转MK801诱导的小鼠分裂样疾病，缓解精神分裂症患者的症状。我们的工作表明，七氟醚可能是治疗精神分裂症患者的一种有价值的治疗策略。
GABAergic deficits have been considered to associate with the pathophysiology of schizophrenia and hence GABA receptors subtype A (GABAARs) modulators such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients.Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day, 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane for 5 hrs per day for 6 days and were assessed with Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2.MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered the amplitude and frequency of mEPSCs and mIPSCs and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was significantly decreased by 38% at 2nd week (p < 0.01).Low-concentration sevoflurane effectively reversed MK801-induced schizophrenia-like disease in mice and alleviated schizophrenia patients’ symptoms. Our work suggested that sevoflurane may be a valuable therapeutic strategy for treating schizophrenia patients.