抑制磷脂酶D1活性可促进缺血性脑卒中模型小鼠神经功能恢复

doi:10.12300/j.issn.1674-5817.2022.041

实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (4): 322-332.DOI: 10.12300/j.issn.1674-5817.2022.041

抑制磷脂酶D1活性可促进缺血性脑卒中模型小鼠神经功能恢复

朱彦兵¹^,²(), 白帆³^,⁴, 陶少鑫¹^,², 潘雨花蕾¹^,², 王欢¹, 赵羽商¹, 王崧¹, 于艳³^,⁴()()

^1.北京市临床医学研究所, 首都医科大学附属北京友谊医院, 北京 100050
^2.首都医科大学附属北京友谊医院神经内科, 北京 100050
^3.中国康复研究中心中国康复科学所, 北京 100068
^4.神经损伤与康复北京市重点实验室, 北京 100068

收稿日期:2022-03-29 修回日期:2022-05-19 出版日期:2022-08-25 发布日期:2022-09-01
通讯作者: 于艳（1981—），女，博士，副研究员，研究方向为神经生物学。E-mail：yuyancrrc@163.com。ORCID：0000-0001-5377-8631
作者简介:朱彦兵（1980—），男，博士，副研究员，研究方向为神经生物学。E-mail：zhuyanbing@ccmu.edu.cn
基金资助:
国家自然科学基金面上项目“磷脂酶D在脑卒中后反应性星形胶质细胞增殖和分泌中的作用及其机制研究”(81771235);中央级公益性科研院所基本科研业务费专项资金项目“磷脂酶D在脑卒中后神经元过度自噬中的作用以及机制研究”(2019CZ-14)

Inhibition of Phospholipase D1 Activity Improves the Recovery of Neurological Function in Mice with Ischemic Stroke

Yanbing ZHU¹^,²(), Fan BAI³^,⁴, Shaoxin TAO¹^,², Yuhualei PAN¹^,², Huan WANG¹, Yushang ZHAO¹, Song WANG¹, Yan YU³^,⁴()()

^1.Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
^2.Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
^3.China Rehabilitation Science Institute, China Rehabilitation Research Center, Beijing 100068, China
^4.Beijing Key Laboratory of Neural Injury and Neural Rehabilitation, Beijing 100068, China

Received:2022-03-29 Revised:2022-05-19 Published:2022-08-25 Online:2022-09-01
Contact: YU Yan (ORCID: 0000-0001-5377-8631), E-mail: yuyancrrc@163.com

摘要/Abstract

摘要：

目的探讨小鼠缺血性脑卒中发生后不同时期病灶脑组织自噬的动态变化，以及抑制磷脂酶D（phospholipase D，PLD）1活性与自噬及神经功能的关系。方法先用21只8周龄成年雄性C57BL/6小鼠构建缺血性脑卒中模型，随机分为假手术组和缺血性脑卒中后4 h、6 h、8 h、12 h、24 h、72 h组，每组各3只，采用蛋白质印迹法和免疫荧光染色法检测小鼠病灶脑组织中自噬相关蛋白LC3的表达及分布情况。另将36只8周龄成年雄性C57BL/6小鼠随机分为假手术组、缺血性脑卒中后腹腔注射PBS组和4个浓度（0.3、0.9、1.8和3.6 mg/kg）的PLD活性抑制剂FIPI组，每组各6只；缺血性脑卒中发生后的第1、第3和第7天，分别通过贴纸去除实验、触须诱发前肢放置实验和TTC染色法评估抑制剂最佳浓度及其对神经功能和脑梗死面积的影响。再将9只8周龄成年雄性C57BL/6小鼠随机分为假手术组、缺血性脑卒中后立即腹腔注射PBS和0.9 mg/kg FIPI组，每组3只，通过蛋白质印迹法检测FIPI对自噬相关蛋白表达的影响。最后将36只8周龄成年雄性C57BL/6小鼠随机分为假手术组、缺血性脑卒中后立即腹腔注射PBS组以及不同时间窗（术后立即和术后4 h、8 h、12 h）腹腔注射0.9 mg/kg FIPI组，每组各6只，通过行为学实验和TTC染色法评估缺血性脑卒中小鼠的神经功能和脑梗死面积。结果小鼠缺血性脑卒中发生后，病灶组织中LC3-Ⅱ相对表达水平开始升高，24 h达到峰值（P＜0.05），然后逐渐下降。与PBS组相比，给予0.9 mg/kg的 PLD1活性抑制剂FIPI组能明显抑制小鼠缺血性脑卒中后病灶组织中LC3-Ⅱ相对表达水平（P＜0.05），缩小梗死面积（P＜0.05），促进损伤后神经功能的恢复（P＜0.05）。与PBS组相比，除了缺血性脑卒中后立即给予FIPI组外，缺血性脑卒中后4 h、8 h和12 h腹腔给予FIPI也都可以明显缩小梗死面积（P＜0.05），使小鼠神经功能得到明显恢复（P＜0.05）。结论缺血性脑卒中发生后24 h病灶组织自噬最为明显，降低PLD1活性可以明显抑制自噬，从而促进缺血性脑卒中后神经功能的恢复。同时，除了缺血性脑卒中后立即给予FIPI外，延迟4～12 h给予FIPI也可以缩小梗死面积，促进神经功能的恢复，这拓宽了缺血性脑卒中的治疗窗口期，可能为临床治疗脑卒中提供新的策略。

关键词: 缺血性脑卒中, 自噬, 磷脂酶D1, 神经功能, C57BL/6小鼠

Abstract:

Objective To investigate the dynamic changes of autophagy in infarcted cortex at different stages after ischemic stroke, and the relationship between phospholipase D1 (PLD1) activity, autophagy, and the neurological function in mice. Methods Firstly, twenty-one male C57BL/6 mice at age of 8 weeks were used to establish ischemic stroke models, and they were randomly divided into sham surgery and ischemic stroke groups. The groups were furtherly divided into 4-, 6-, 8-, 12-, 24-, and 72-hour groups according to the onset of ischemic strok with three mice in each group. Dynamic expression and change of autophagy-related protein LC3 in the infarcted cortex were observed using Western blotting method and immunofluorescence staining. Secondly, thirty-six male C57BL/6 mice at age of 8 weeks were randomly divided into the sham surgery group, the PBS treatment group, and different concentrations of phospholipase D activity inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) treatment groups containing 0.3, 0.9, 1.8, and 3.6 mg/kg, respectively. Each group comprised six mice. The optimal FIPI concentration and its effects on neurological function and infarcted volume were assessed by adhesive removal and whisker tests and TTC staining. Furthermore, nine male C57BL/6 mice at age of 8 weeks were divided into sham surgery group, intraperitoneal administration of PBS group, and 0.9 mg/kg FIPI group. Each group comprised three mice. The effects of FIPI on changes in autophagy-related protein LC3 were examined by Western blotting. Finally, thirty-six adult male C57BL/6 mice at age of 8 weeks were divided into sham surgery group, intraperitoneal administration of PBS group, and 0.9 mg/kg FIPI treatment groups at four time points (0, 4, 8, and 12 hours) after ischemic stroke. Furthermore, the neurological functions and infarcted volume were assessed by the adhesive removal and whisker tests as well as TTC staining with six mice in each group. Results The ratio of LC3-Ⅱ/β-actin in the infarcted cortex increased, peaked at 24 hours (P＜0.05), and then gradually declined after ischemic stroke. Compared with the PBS group, the administration of 0.9 mg/kg FIPI significantly decreased the ratio of LC3-Ⅱ/β-actin (P＜0.05), reduced the infarcted area (P＜0.05), and ameliorated neurological functions (P＜0.05) more than those observed in the other concentration groups. Compared with the PBS group, in addition to 0.9 mg/kg FIPI without delay, the administration of 0.9 mg/kg FIPI at 4-, 8-, and 12-hour after ischemic stroke could also decrease the infracted volume (P＜0.05) and improve the neurological function (P＜0.05). Conclusion The change of autophagy was the most obvious at 24-hour after ischemic stroke and inhibition of PLD1 could improve the recovery of neurological function after ischemic stroke. Meanwhile, in addition to administration of 0.9 mg/kg FIPI without delay, 4-, 8-, and 12-hour after ischemic stroke could also shrink the infracted volume and improve the neurological function. The inhibition of the PLD1 could extend the therapeutic window and provide a novel therapeutic strategy for the clinical treatment of cerebral stroke.

Key words: Ischemic stroke, Autophagy, Phospholipase D1, Neurological function, C57BL/6 mice

中图分类号:

R-332

朱彦兵, 白帆, 陶少鑫, 潘雨花蕾, 王欢, 赵羽商, 王崧, 于艳. 抑制磷脂酶D1活性可促进缺血性脑卒中模型小鼠神经功能恢复[J]. 实验动物与比较医学, 2022, 42(4): 322-332.

Yanbing ZHU, Fan BAI, Shaoxin TAO, Yuhualei PAN, Huan WANG, Yushang ZHAO, Song WANG, Yan YU. Inhibition of Phospholipase D1 Activity Improves the Recovery of Neurological Function in Mice with Ischemic Stroke[J]. Laboratory Animal and Comparative Medicine, 2022, 42(4): 322-332.

图/表 5

图1 蛋白质印迹法（A～B）和免疫荧光染色法（C～D）检测缺血性脑卒中小鼠病灶组织中自噬相关蛋白LC3的表达情况注：A为缺血性脑卒中发生后不同时间点（4～72 h）自噬相关蛋白LC3 的表达情况；B为LC3-Ⅱ/β-actin比值随缺血性脑卒中发生不同时间的变化（每个时间点均3只小鼠，*P＜0.05）。C和D分别为共聚焦显微镜下观察假手术组和缺血性脑卒中发生后24 h组的LC3-Ⅱ分布情况（箭头所指为聚集状膜型LC3-Ⅱ，标尺为10 μm）。

Figure 1 Expression of autophagy-related LC3 in the infracted cortex after ischemic stroke detected by Western blotting (A and B) and immunofluorescent staining (C and D)Note: A is the level of autophagy-related protein LC3 at different time points （4-72 h）. B is the statistical analysis of the ratio of LC3-Ⅱ/β-actin at different time points (n=3 at each time point, *P＜0.05). C is the morphology of LC3 in the sham group. D is the morphology of LC3 in 24-hour group after ischemic stroke (the arrow points for LC3-Ⅱ, and the scale bar is 10 μm).

图2 行为学实验显示缺血性脑卒中后给予0.9 mg/kg抑制剂FIPI后可以明显促进小鼠神经功能的恢复注：A～C图为贴纸去除实验，以左脚掌上的贴纸持续时间反映小鼠神经功能；D～F组为触须诱发前肢放置实验，以左前肢触发成功率反映小鼠神经功能。A和D为小鼠缺血脑卒中发生第1天的行为学实验结果；B和E为小鼠缺血性脑卒中发生第3天的行为学实验结果；C和F为小鼠缺血性脑卒中发生第7天的行为学实验结果。每组6只小鼠；*P<0.05，**P<0.01，***P<0.001，****P<0.000 1，表示组间有明显差异；ns表示没有组间差异无统计学意义。FIPI为磷脂酶D活性抑制剂。

Figure 2 Behavior tests reveal administration of 0.9 mg/kg FIPI after ischemic stroke obviously improves neurological function of miceNote: A, B, and C denote adhesive removal tests (detecting latency time of left paw); D, E, and F are whisker tests (detecting success percentage of left forelimb). A and D show the behavior tests on the 1st day; B and E show the behavior tests on the 3rd day; C and F show the behavior tests on the 7th day. n=6 in each group; *P<0.05, **P<0.01, ***P<0.001, ****P<0.000 1; ns, not significant. FIPI, 5-fluoro-2-indolyl deschlorohalopemide, is a phospholipase D inhibitor.

图3 蛋白质印迹法（A～B）和TTC染色法（C～D）分别检测抑制剂FIPI给药对缺血性脑卒中小鼠病灶组织中自噬相关蛋白LC3表达及梗死面积的影响注：A为自噬相关蛋白LC3的蛋白质印迹结果；B为LC3-Ⅱ/β-actin比值变化的统计分析结果（每组3只小鼠，*P＜0.05，**P＜0.01）。C为缺血性脑卒中后小鼠脑组织的TTC染色结果，白色为梗死病灶组织，红色为正常脑组织；D为梗死面积的统计分析结果（每组6只小鼠，*P<0.05）。FIPI为磷脂酶D活性抑制剂。

Figure 3 Expression of autophagy-related LC3 and the change in the infarcted cortex volume after FIPI inhibitor treatment are detected by Western blotting (A and B) and TTC staining (C and D)Note: A is the level of autophagy-related protein LC3 at different time points; B is the statistical analysis of the ratio of LC3-Ⅱ/β-actin (n=3 in each group, *P＜0.05, **P＜0.01). C is the TTC staining of the infarcted cortex in two groups; white color indicates the infarcted cortex and red color indicates the normal cortex; D is the statistical analysis of the infarcted cortex area (n=6 in each group, *P<0.05). FIPI, 5-fluoro-2-indolyl deschlorohalopemide, is a phospholipase D inhibitor.

图4 行为学实验显示缺血性脑卒中后不同时间点给予0.9 mg/kg抑制剂FIPI均可以明显促进神经功能的恢复注：A～C图为贴纸去除实验，以左脚掌上的贴纸持续时间反映小鼠神经功能；D～F组为触须诱发前肢放置实验，以左前肢触发成功率反映小鼠神经功能。A和D为小鼠缺血脑卒中发生第1天的行为学实验结果；B和E为小鼠缺血性脑卒中发生第3天的行为学实验结果；C和F为小鼠缺血性脑卒中发生第7天的行为学实验结果。每组6只小鼠；组间差异，*P<0.05，**P<0.01，***P<0.001，****P<0.000 1。FIPI为磷脂酶D活性抑制剂。

Figure 4 Behavior tests reveal the administration of 0.9 mg/kg FIPI at different time points after ischemic stroke can improve the neurological function of miceNote: A, B, and C denote adhesive removal tests (detecting latency time of left paw); D, E, and F are whisker tests (detecting success percentage of left forelimb). A and D show the behavior tests on the 1st day; B and E show the behavior tests on the 3rd day; C and F show the behavior tests on the 7th day. n=6 in each group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.000 1; ns, not significant. FIPI, 5-fluoro-2-indolyl deschlorohalopemide, is a phospholipase D inhibitor.

图5 TTC染色观察缺血性脑卒中发生后不同时间点给予0.9 mg/kg抑制剂FIPI缩小小鼠脑梗死面积注：A为缺血性脑卒中后不同组小鼠脑组织的TTC染色结果，白色为梗死病灶组织，红色为正常脑组织。B为梗死面积的统计分析结果（每组6只小鼠，*P<0.05）。FIPI为磷脂酶D活性抑制剂。

Figure 5 TTC staining reveals the administration of 0.9 mg/kg FIPI at different time points after ischemic stroke can reduce the volume of infarcted cortex of miceNote: A is the TTC staining of the infarcted cortex in different groups; white color indicates the infarcted cortex and red color indicates the normal cortex; B is the statistical analysis of the infarcted cortex volume (n=6 in each group,*P<0.05). FIPI, 5-fluoro-2-indolyl deschlorohalopemide, is a phospholipase D inhibitor.

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抑制磷脂酶D1活性可促进缺血性脑卒中模型小鼠神经功能恢复

Inhibition of Phospholipase D1 Activity Improves the Recovery of Neurological Function in Mice with Ischemic Stroke

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