2022 年第 1 期 第 17 卷

丁苯酞对帕金森病伴抑郁小鼠抑郁行为的影响及对黑质纹状体相关信号通路的调节作用

Effect of butylphthalide on depressive behavior in mice with Parkinson′s disease and depression and itsregulation of correlated signal pathway in substantia nigra striatum

作者：刘斌1范少凯1李炳翰1杨浩辉1张艳淑2毛文静1邓春颖1吴小坤1王雅楠1李世英1

英文作者：Liu Bin1 Fan Shaokai1 Li Binghan1 Yang Haohui1 Zhang Yanshu2 Mao Wenjing1 Deng Chunying1 Wu Xiaokun1 Wang Yanan1 Li Shiying1

单位：1华北理工大学附属医院神经内科，河北省唐山市063000；2华北理工大学实验动物中心，河北省唐山市063000

英文单位：1Department of Neurology North China University of Science and Technology Affiliated Hospital Hebei Province Tangshan 063000 China; 2Laboratory Animal Center North China University of Science and Technology Hebei Province Tangshan 063000 China

关键词：帕金森病；抑郁；丁苯酞；磷脂酰肌醇-3-激酶/蛋白激酶B/叉头状转录因子O亚族3a信号通路（PI3K/Akt/FoxO3a信号通路）

英文关键词：Parkinson′sdisease;Depression;Butylphthalide;Phosphoinositide-3-kinase/proteinkinaseB/forkheadtranscriptionfactorOsubfamily3asignalingpathway(PI3K/Akt/FoxO3asignalingpathway)

• 摘要：

• 目的 观察丁苯酞对帕金森病伴抑郁小鼠抑郁行为的影响及对黑质纹状体区磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(Akt)/叉头状转录因子O亚族3a（FoxO3a）信号通路关键因子的调节作用，探讨丁苯酞治疗帕金森病抑郁的效果及机制。方法 选择C57成年雄性小鼠40只，完全随机分为正常对照组、帕金森病伴抑郁模型组、多巴丝肼治疗组和联合治疗组。正常对照组正常饲养，不给予任何干预。采用腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶建立帕金森病小鼠模型，采用慢性不可预知温和应激诱导产生帕金森病伴抑郁小鼠模型。多巴丝肼治疗组给予多巴丝肼6.25 mg/kg，1次/d，灌胃7 d；联合治疗组给予多巴丝肼6.25 mg/kg和丁苯酞120 mg/kg，1次/d，灌胃7 d。通过强迫游泳测试、悬尾测试和糖水偏好实验对小鼠的抑郁行为进行评价。蛋白质印迹法检测各组黑质纹状体区PI3K/Akt/FoxO3a信号通路相关磷酸化因子p-PI3K、p-Akt、p-FoxO3a水平。结果 帕金森病伴抑郁模型组强迫游泳不动时间及悬尾静止时间长于正常对照组，糖水偏好指数低于正常对照组，差异均有统计学意义（均P<0.05）。多巴丝肼治疗组及联合治疗组强迫游泳不动时间及悬尾静止时间短于帕金森病伴抑郁模型组，糖水偏好指数高于帕金森病伴抑郁模型组，以联合治疗组更明显，差异均有统计学意义（均P<0.05）。帕金森病伴抑郁模型组p-PI3K、p-Akt、p-FoxO3a表达水平明显低于正常对照组，差异均有统计学意义（均P<0.05）。多巴丝肼治疗组及联合治疗组p-PI3K、p-Akt、p-FoxO3a表达水平高于帕金森病伴抑郁模型组［（0.54±0.02）、（0.60±0.03）比（0.44±0.01），（0.57±0.01）、（0.66±0.02）比（0.44±0.04），（0.61±0.03）、（0.70±0.03）比（0.45±0.02）］，以联合治疗组更明显，差异均有统计学意义（均P<0.05）。结论  丁苯酞可通过激活黑质纹状体区PI3K/Akt/FoxO3a信号通路改善帕金森病伴抑郁小鼠的抑郁症状。

• Objective   To observe the effect of butylphthalide on depressive behavior in mice with Parkinson′s disease and depression and its regulation of key factors of phosphoinositide-3-kinase(PI3K)/protein kinase B(Akt)/forkhead transcription factor O subfamily 3a(FoxO3a) signal pathway in substantia nigra striatum, and to explore the effect and mechanism of butylphthalide on the treatment of Parkinson′s disease depression. Methods  Totally 40 C57 adult male mice were selected and randomly divided into normal control group, Parkinson′s disease with depression model group, levodopa and benserazide hydrochloride(LD/BH) treatment group and combined treatment group. The normal control group was fed normally without any intervention. Parkinson′s disease mouse model was established by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneal injection, and the mouse model of Parkinson′s disease with depression was induced by chronic unpredictable mild stress. LD/BH treatment group was given LD/BH 6.25 mg/kg, once a day, intragastrically for 7 d; combined treatment group was given LD/BH 6.25 mg/kg and butylphthalide 120 mg/kg once a day, intragastrically for 7 d. The depressive behavior of mice was evaluated by forced swimming test, tail suspension test and sugar preference test. The levels of phosphorylation factors p-PI3K, p-Akt and p-FoxO3a related to PI3K/Akt/FoxO3a signaling pathway in substantia nigra striatum were detected by western blotting. Results  The forced swimming immobility time and tail suspension rest time in the Parkinson′s disease with depression model group were longer than those in the normal control group, and the sugar preference index was lower than that in the normal control group(all P<0.05). The forced swimming immobility time and tail suspension rest time in the LD/BH treatment group and combined treatment group were shorter than those in the Parkinson′s disease with depression model group, and the sugar preference index was higher than that in the Parkinson′s disease with depression model group, especially in the combined treatment group(all P<0.05). The expression levels of p-PI3K, p-Akt and p-FoxO3a in the Parkinson′s disease with depression model group were lower than those in the normal control group(all P<0.05). The expression levels of p-PI3K, p-Akt and p-FoxO3a in the LD/BH treatment group and combined treatment group were higher than those in the Parkinson′s disease with depression model group［（0.54±0.02）,（0.60±0.03） vs （0.44±0.01）; （0.57±0.01）, （0.66±0.02） vs （0.44±0.04）; （0.61±0.03）, （0.70±0.03） vs （0.45±0.02）］, especially in the combined treatment group(all P<0.05). Conclusion  Butylphthalide can improve the depressive symptoms of Parkinson′s disease with depression mice by activating PI3K/Akt/FoxO3a signaling pathway in substantia nigra striatum.