柴胡疏肝散改善肝气郁结型大鼠抑郁症的机制：基于microPET_CT方法.pdf

Mechanism of Chaihu Shugan powder in improving depression rats with liver-qistagnation based on microPET/CTWANG Wei1,CHEN Yingmao2,WANG Yulai3,GUO Rongjuan3,WANG Luqi4,CONG Junjie1,HE Lijuan11Department of Rehabilitation,3Department of Brain Disease,4Department of Cardiovascular,Dongfang Hospital,Beijing University ofChinese Medicine,Beijing 100078,China;2Department of Nuclear Medicine,Chinese PLA General Hospital,Beijing 100853,China摘要：目的 观察柴胡疏肝散对肝气郁结型抑郁症大鼠行为改善，并探索其临床疗效机制是否是通过改善脑葡萄糖代谢发挥抗抑郁作用。方法 雄性Wistar大鼠40只，按体质量匹配原则随机分为对照组、模型组和柴胡疏肝散高、低剂量组，10只/组，运用慢性束缚应激结合孤养法建立肝气郁结型大鼠模型，柴胡疏肝散高、低剂量组分别用1.04 g/mL及0.52 g/mL的浓缩药液灌胃，对照组与模型组用生理盐水灌胃，灌胃从实验开始之日起，1次/d，持续21 d。观察旷场实验和糖水偏好实验变化，使用小型正电子发射断层显像与CT摄影融合术观察大鼠感兴趣脑区的脑葡萄糖代谢变化。结果 行为学提示：与对照组相比，模型组大鼠糖水偏好程度下降（P0.05），旷场实验不动时间延长（P0.05）。脑代谢提示：模型组代谢增高脑区：双侧延髓、左侧小脑（P0.05），代谢减低脑区：双侧胼胝体、双侧M1、双侧M2、左侧纹状体、右侧丘脑、右侧海马、右侧前额叶皮质、右侧扣带皮质、右侧S1、右侧S2、右侧岛叶皮质（P0.05）。与模型组相比，高、低剂量组糖水偏好程度增高（P0.05），旷场实验不动时间减少（P0.05）；低剂量组代谢增高脑区：双侧纹状体、双侧海马、双侧胼胝体、双侧前额叶皮质、左侧下丘、左侧M2、右侧听觉皮质、右侧丘脑、右侧M1、右侧S1、右侧S2、右侧岛叶皮质（P0.05），代谢减低脑区：左侧延髓、左侧视觉皮质、左侧小脑（P0.05）；高剂量组代谢增高脑区：右侧前额叶皮质（P0.05）。结论 肝气郁结证发病机制为慢性应激结合孤养法降低情绪认知和行为调节相关脑区葡萄糖代谢，使之失代偿，同时使左脑纹状体、小脑脑区发生葡萄糖摄取竞争，柴胡疏肝散可改善肝气郁结型抑郁症大鼠行为，其主要通过改善与情绪认知、行为等相关脑区及改善左脑纹状体、小脑脑区葡萄糖摄取竞争从而发挥抗抑郁效应。关键词：抑郁症；肝气郁结证；柴胡疏肝散；microPET/CTAbstract:Objective To investigate the effects of Chaihu Shugan powder on the behavior of rats with liver-qi stagnationdepression and to explore the potential antidepressant mechanism of Chaihu Shugan powder through the improvement ofbrain glucose metabolism.Methods Forty male Wistar rats were randomly divided into control group,model group,low-doseChaihu Shugan powder group,and high-dose Chaihu Shugan powder group,with 10 rats per group.A rat model of liver-qistagnation was established by using chronic restraint stress combined with solitary rearing.The high and low dose ChaihuShugan powder groups were administered 1.04 g/mL and 0.52 g/mL concentrated solutions by gavage,respectively.The controland model groups were treated with normal saline by gavage once daily for 21 days from the beginning of the experiment.Results Behavioral indicators:Compared with the control group,the sucrose preference of the rats in the model groupsignificantly decreased(P0.05),and the immobility time in the open field test significantly increased(P0.05).Brainmetabolism indicators:The brain regions with increased metabolism in the model group were the bilateral medulla oblongataand left cerebellum(P0.05),while the brain regions with decreased metabolism included bilateral corpus callosum,bilateralM1,bilateral M2,left striatum,right thalamus,right hippocampus,right prefrontal cortex,right cingulate cortex,right S1,rightS2,and right insular cortex(P0.05).In comparison with the model group,both high-and low-dose groups showed asignificant increase in sucrose preference(P0.05)and a significant decrease in immobility time in the open field test(P0.05).In the low-dose group,the brain regions with increased metabolism encompassed bilateral striatum,bilateral hippocampus,bilateral corpus callosum,bilateral prefrontal cortex,left inferior colliculus,left M2,right auditory cortex,right thalamus,rightM1,right S1,right S2,right insular cortex(P0.05),whereas the brain regions with decreased metabolism included leftmedulla,left visual cortex,and left cerebellum(P0.05).The high-dose group displayed increased metabolism in the rightprefrontal cortex(P0.05).Conclusion Thepathogenesis of liver-qi stagnation syndrome may involve chronic stress combined with isolation,resulting in decreasedglucose metabolism in brain regions related to emotional cognition and behavioral regulation,leading to decompensation andconcurrent glucose uptake competition in the left striatum and cerebellar brain regions.Chaihu Shugan powder can improvethebehaviorofratswithliver-qistagnationdepressionbyexertingitsantidepressanteffectprimarilythroughenhancementofemotionalcognition and behavioral-related brain regions,andameliorating glucose uptake competition in the leftstriatum and cerebellar brain regions.Keywords:depression;liver-qistagnation;ChaihuShugan powder;microPET/CT柴胡疏肝散改善肝气郁结型大鼠抑郁症的机制柴胡疏肝散改善肝气郁结型大鼠抑郁症的机制：基于基于microPET/microPET/C CT T方法方法王 伟1，陈英茂2，王玉来3，郭蓉娟3，王璐绮4，丛俊婕1，贺立娟1北京中医药大学东方医院1康复科，3脑病科，4心血管科，北京 100078；2中国人民解放军总医院核医学科，北京100853收稿日期：2023-04-25基金项目：国家自然科学基金（30973706）Supported by National Nature Science Foundation of China(30973706)作者简介：王 伟，在读硕士研究生，E-mail:通信作者：贺立娟，博士，副主任医师，E-mail:分子影像学杂志,2023,46(4):575-582doi 10.12122/j.issn.1674-4500.2023.04.01 575抑郁症是以情绪低落、兴趣减退为主要临床表现的一种精神疾病，我国抑郁症患者数量约占全世界的1/31。抑郁症归于中医“情志病”范畴，在中医古籍中以“脏躁”、“百合病”、“癫”及“梅核气”等病名出现，中医药治疗抑郁症疗效显著，复发率低，可有效改善患者精神和躯体症状2，但其证候及治疗机制尚不明确。柴胡疏肝散出自 景岳全书，全方由柴胡、白芍、川芎、枳壳、陈皮、香附、甘草组成，共奏疏肝解郁，活血行气止痛之功，其临床用于治疗汗证3、桥本甲状腺炎4、抑郁症5等多种疾病，其治疗抑郁症疗效较普通西药疗效好，安全性高6，其包含多种化学成分，通过升高神经递质水平、增加神经营养因子及其受体表达、抑制神经内分泌轴亢进、调节炎症因子平衡以及调节肠道菌群种类和丰度等，发挥抗抑郁作用7。影像学的发展丰富了对人体内部的观察，当前关于抑郁症中医证候内涵的影像学研究涉及MRI、CT、脑电图、超声及数字减影血管造影等，但其结果多涉及大脑沟回的可视化分析8，未对其代谢机制进行研究。本实验使用慢性束缚联合孤养法建立肝气郁结型抑郁症大鼠模型，使用microPET/CT从脑葡萄糖代谢角度探究肝气郁结型抑郁症的中医证候内涵及柴胡疏肝散对其调控机制及影