熊果酸改善精神分裂症小鼠脱髓鞘和脑组织间液引流紊乱  

Ursolic acid improved demyelination and interstitial fluid drainage disorders in schizophrenia mice

作　　者：龙仁 毛鑫 高天姿 解倩[2] 谈瀚博 李子寅 韩鸿宾[1,2] 袁兰[1] LONG Ren;MAO Xin;GAO Tianzi;XIE Qian;TAN Hanbo;LI Ziyin;HAN Hongbin;YUAN Lan(Department of Medical Imaging Technology,Institute of Medical Technology,Peking University&Beijing Key Lab of Magnetic Resonance Imaging Device and Technique,Beijing 100191,China;Department of Radiology,Peking Univer-sity Third Hispital,Beijing 100191,China)

机构地区：[1]北京大学医学技术研究院医学影像技术学系,北京市磁共振成像设备与技术重点实验室,北京100191 [2]北京大学第三医院放射科,北京100191

出　　处：《北京大学学报（医学版）》2024年第3期487-494,共8页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(62394310、62394312、62394314)。

摘　　要：目的:探讨精神分裂症(schizophrenia,SZ)的髓鞘和脑组织间液(interstitial fluid,ISF)相关发病机制,探究熊果酸(ursolic acid,UA)对SZ中髓鞘损伤及其继发的ISF异常引流的治疗效果。方法:使用30只6~8周雌性C57BL/6J小鼠,体质量(20±2)g,随机分为UA治疗组、SZ模型组、对照组3组,每组10只:(1)对照组:腹腔注射(intraperitoneal injection,ip)生理盐水,灌胃(intragastric,ig)给予1%(质量分数)羧甲基纤维素钠(carboxymethylcellulose sodium,CMC-Na);(2)SZ模型组:ip给与2 mg/kg的地卓西平(dizocilpine maleate,MK-801),ig给与1%(质量分数)CMC-Na;(3)UA治疗组:ig给与25 mg/kg的UA,ip给与2 mg/kg的MK-801。治疗组先ig给药UA预治疗一周,然后对3组小鼠进行为期两周的药物干预。在造模完成后依次通过旷场测试和前脉冲抑制实验对小鼠进行行为学评价。行为测试后,通过向脑区注射荧光示踪剂来探究各组ISF分区引流的改变;通过免疫荧光探究各组脑内水通道蛋白4(aquaporin 4,AQP4)极性分布的改变以及蛋白表达的变化;通过激光共聚焦显微镜(laser scanning confocal microscope,LSCM)髓鞘反射光成像研究鼠脑内髓鞘的变化。采用单因素方差分析(one-way ANOVA)对计量数据进行组间比较,使用TukeyHSD进行组间两两比较。结果:旷场测试发现,模型组在旷场中运动的总路程[(7949.39±1140.55)cm vs.(2831.01±1212.72)cm,P<0.001]和中央区域停留时间[(88.43±22.06)s vs.(56.85±18.58)s,P=0.011]显著高于对照组,而治疗组在旷场中运动总路程[(2415.80±646.95)cm vs.(7949.39±1140.55)cm,P<0.001]和中央区域停留时间[(54.78±11.66)s vs.(88.43±22.06)s,P=0.007]较模型组显著降低。前脉冲抑制实验发现,模型组给与预脉冲时对震惊反射的抑制率均显著低于对照组(P均<0.001);治疗组上述指标较模型组显著增加(P均<0.001)。髓鞘反射光检测发现,模型组小鼠脑内存在显著的脱髓鞘,治疗组脑内脱髓鞘情况得到逆转。荧光示踪发�Objective:To unveil the pathological changes associated with demyelination in schizophrenia(SZ)and its consequential impact on interstitial fluid(ISF)drainage,and to investigate the therapeutic efficacy of ursolic acid(UA)in treating demyelination and the ensuing abnormalities in ISF drainage in SZ.Methods:Female C57BL/6J mice,aged 6-8 weeks and weighing(20±2)g,were randomly divided into three groups:control,SZ model,and UA treatment.The control group received intraperitoneal injection(ip)of physiological saline and intragastric administration(ig)of 1%carboxymethylcellulose sodium(CMC-Na).The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate(MK-801)and ig administration of 1%CMC-Na.The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801.The treatment group received UA pretreatment via ig administration for one week,followed by a two-week drug intervention for all the three groups.Behavioral assessments,including the open field test and prepulse inhibition experiment,were conducted post-modeling.Subsequently,changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions.Immunofluorescence analysis was employed to examine alterations in aquaporin 4(AQP4)polarity distribution in the brain and changes in protein expression.Myelin reflex imaging using Laser Scanning Confocal Microscopy(LSCM)was utilized to study modifications in myelin within the mouse brain.Quantitative data underwent one-way ANOVA,followed by TukeyHSD for post hoc pairwise comparisons between the groups.Results:The open field test revealed a significantly longer total distance[(7949.39±1140.55)cm vs.(2831.01±1212.72)cm,P<0.001]and increased central area duration[(88.43±22.06)s vs.(56.85±18.58)s,P=0.011]for the SZ model group compared with the controls.The UA treatment group exhibited signifi-cantly reduced total distance[(2415.80±646.95)cm vs.(7949.39±1140.55)cm,P<0.001]and increased central area duration[(54.78±11

关 键 词：精神分裂症 脑组织间液 脱髓鞘 熊果酸 

分 类 号：R285.5[医药卫生—中药学]