载脂蛋白E拟肽COG1410对蛛网膜下腔出血后自噬和凋亡的影响

黎新慎; 彭建华; 庞金伟; 李勇; 周牮; 古龙; 吴越; 黄学平; 孙晓川; 陈礼刚; 江涌

doi:10.16016/j.1000-5404.201708137

您当前的位置：

首页 >

文章列表页 >

载脂蛋白E拟肽COG1410对蛛网膜下腔出血后自噬和凋亡的影响

基础医学 | 更新时间：2026-01-09

- 载脂蛋白E拟肽COG1410对蛛网膜下腔出血后自噬和凋亡的影响
- Effects of apolipoprotein E mimetic peptide COG1410 on central autophagy and apoptosis after subarachnoid hemorrhage in mice
- 第三军医大学学报 2017年39卷第24期页码：2366-2373
- 作者机构：
  
  1.646000 四川泸州，西南医科大学附属医院神经外科
  2.400016 重庆，重庆医科大学附属第一医院神经外科
  3.646000 四川泸州，泸州市人民医院神经外科
- 作者简介：
  
  [江涌，E-mail：jiangyong@swmu.edu.cnJIANG Yong, E-mail:jiangyong@swmu.edu.cn
- 基金信息：
  
  国家自然科学基金面上项目(81371319);泸州市政府-西南医科大学联合项目(2016LZXNYD-Z02);泸州市政府-西南医科大学联合项目(2016LZXNYD-J12)
- DOI：10.16016/j.1000-5404.201708137
  中图分类号： R341; R394.1; R734.35
- 收稿：2017-08-24，
  
  修回：2017-09-06，
  
  纸质出版：2017-12-30
- 稿件说明：
移动端阅览
黎新慎, 彭建华, 庞金伟, 等. 载脂蛋白E拟肽COG1410对蛛网膜下腔出血后自噬和凋亡的影响[J]. 第三军医大学学报, 2017,39(24):2366-2373.

Xinshen LI, Jianhua PENG, Jinwei PANG, et al. Effects of apolipoprotein E mimetic peptide COG1410 on central autophagy and apoptosis after subarachnoid hemorrhage in mice[J]. Journal of Third Military Medical University, 2017, 39(24): 2366-2373.
黎新慎, 彭建华, 庞金伟, 等. 载脂蛋白E拟肽COG1410对蛛网膜下腔出血后自噬和凋亡的影响[J]. 第三军医大学学报, 2017,39(24):2366-2373. DOI： 10.16016/j.1000-5404.201708137.

Xinshen LI, Jianhua PENG, Jinwei PANG, et al. Effects of apolipoprotein E mimetic peptide COG1410 on central autophagy and apoptosis after subarachnoid hemorrhage in mice[J]. Journal of Third Military Medical University, 2017, 39(24): 2366-2373. DOI： 10.16016/j.1000-5404.201708137.

摘要

目的

研究新一代载脂蛋白(apolipoprotein E，apoE)拟肽COG1410的应用对蛛网膜下腔出血(subarachnoid hemorrhage

SAH)后早期脑损伤(early brain injury

EBI)期间大脑自噬及凋亡的影响。

方法

选用颈内动脉穿刺法建立小鼠SAH模型，首先观察EBI期间伤侧大脑半球自噬、凋亡及相关信号蛋白的表达变化，然后针对自噬水平最活跃的时间点进行COG1410给药，采取Garcia评分评价SAH及给药后小鼠的神经功能变化，利用Western blot测定自噬、凋亡及相关信号分子蛋白的表达量，并使用免疫荧光染色观察皮层神经元的凋亡变化情况。

结果

① 在SAH后EBI期间，与Sham组相比，伤侧大脑半球的自噬水平在SAH后6 h开始增加(

＜0.05)，并在24 h达到高峰(

＜0.01)，随后逐渐下降，信号分子p-GSK-3β水平也有类似的变化趋势；给予小鼠COG1410后，SAH后24 h的大脑自噬活动被进一步增强(

＜0.05)。②在SAH后的EBI期间，伤侧大脑半球整体凋亡水平变化并不完全和自噬及p-GSK-3β水平变化同步，其在EBI后期仍保持相对高值，但有减弱的趋势；给予COG1410后，伤侧大脑半球和皮层神经元凋亡水平均被下调(

＜0.05)。③与Sham组(16.50±1.05)比较，SAH组的Garcia评分(11.17±1.83)明显降低(

＜0.01)，COG1410的干预能显著改善SAH组的Garcia评分(15.17±0.75)(

＜0.01)，但COG1410的干预对SAH分级影响并不大。

结论

COG1410的应用可能通过磷酸化GSK-3β增强SAH后EBI期间大脑的自噬活动，减弱神经元的凋亡活动，并改善模型小鼠的神经功能。

Abstract

Objective

To determine the effect of a novel apolipoprotein E (apoE) mimetic peptide

COG1410

on the autophagy and apoptosis in early brain injury (EBI) after subarachnoid hemorrhage(SAH).

Methods

Murine model of SAH was established by endovascular perforation in the carotid artery. The changes of autophagy

apoptosis and related signal protein levels in the injured hemisphere were observed.Then

COG1410 was administrated at the time point of relatively strongest autophagy.Neurological function was quantified by Garcia score in the SAH mice before and after COG1410 treatment. The expression levels of autophagy

apoptosis and the related signal protein levels were detected by Western blotting

and the apoptosis of cortical neurons were observed by immunofluorescence staining.

Results

① Compared with the sham group

the autophagy in the injured cerebral hemisphere was increased at 6 h after SAH (

0.05)

peaked at 24 h (

0.01)

and then decreased gradually.The change of p-GSK-3β was in a same trend. Administration of COG1410 at 24 h after SAH resulted in further enhanced autophagy (

0.05). ② In the phase of EBI after SAH

the apoptosis status in t

he injured hemisphere was not completely synchronized with the changes of autophagy and p-GSK-3β level; The apoptosis remained at a relatively high status

though in a trend of decreasing. COG1410 treatment inhibited the apoptosis in the injured hemisphere and the apoptosis of the cortical neurons (

0.05).③The neurological score was significantly lower in the model group than the sham group (11.17±1.83

16.50±1.05

0.01)

but the score was notably improved after the administration of COG1410 (15.17±0.75

0.01).But

the administration showed no obvious effect on the SAH grade.

Conclusion

The administration of COG1410 may promote the brain autophagy but depress the neuronal apoptosis

and improve the neurological function by phosphorylation of GSK-3β in mice in EBI after SAH.

关键词

Keywords

references

VAN GIJN J, RINKEL G J. Subarachnoid haemorrhage: diagnosis, causes and management[J].Brain, 2001, 124(Pt2): 249-278.

KUSAKA G, ISHIKAWA M, NANDA A, et al. Signaling pathways for early brain injury after subarachnoid hemorrhage[J]. J Cereb Blood Flow Metab, 2004, 24(8): 916-925. DOI: 10.1097/01.WCB.0000125886.48838.7E.

CHEN S, WU H, TANG J, et al. Neurovascular events after subarachnoid hemorrhage: focusing on subcellular organelles[J]. Acta Neurochir Suppl, 2015, 120: 39-46. DOI: 10.1007/978-3-319-04981-6_7.

张志鑫, 崔应麟, 李彦杰, 等.骨形成蛋白和激活素的跨膜抑制剂调节自噬抑制谷氨酸诱导的大鼠脊髓背角神经组织细胞凋亡[J].第三军医大学学报, 2017, 39(3): 259-264. DOI: 10.16016/j.1000-5404.201606009.

ZHANG Z X, CUI Y L, LI Y J, et al.BAMBI inhibits apoptosis in glutamate induced neurons and astrocytes in spinal dorsal horn of rats via regulating autophagy[J]. J Third Mil Med Univ, 2017, 39(3): 259-264. DOI: 10.16016/j.1000-5404.201606009.

PALADE C, CIUREA A V, NICA D A, et al. Interference of apoptosis in the pathophysiology of subarachnoid hemorrhage[J]. Asian J Neurosurg, 2013, 8(2): 106-111. DOI: 10.4103/1793-5482.116389.

PARK C H, LEE B H, AHN S G, et al. Serine 9 and tyrosine 216 phosphorylation of GSK-3β differentially regulates autophagy in acquired cadmium resistance[J]. Toxicol Sci, 2013, 135(2): 380-389. DOI: 10.1093/toxsci/kft158.

ENDO H, NITO C, KAMADA H, et al. Akt/GSK3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats[J]. Stroke, 2006, 37(8): 2140-2146. DOI: 10.1161/01.STR.0000229888.55078.72.

HAYASHI H, CAMPENOT R B, VANCE D E, et al. Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1[J]. J Neurosci, 2007, 27(8): 1933-1941. DOI: 10.1523/JNEUROSCI.5471-06.2007.

LASKOWITZ D T, LEI B, DAWSON H N, et al. TheapoE-mimetic peptide, COG1410, improves functional recovery in a murine model of intracerebral hemorrhage[J]. Neurocrit Care, 2012, 16(2): 316-326. DOI: 10.1007/s12028-011-9641-5.

WANG H, ANDERSON L G, LASCOLA C D, et al. ApolipoproteinE mimetic peptides improve outcome after focal ischemia[J]. Exp Neurol, 2013, 241: 67-74. DOI: 10.1016/j.expneurol.2012.11.027.

贺杰, 庞金伟, 吴越, 等.载脂蛋白E短肽COG1410对蛛网膜下腔出血后早期脑水肿的影响[J].第三军医大学学报, 2016, 38(4): 350-355. DOI: 10.16016/j.1000-5404.201508073.

HE J, PANG J W, WU Y, et al.Effect of apolipoprotein E mimetic peptide on cerebral edema in mice at early stage after subarachnoid hemorrhage[J].J Third Mil Med Univ, 2016, 38(4): 350-355. DOI: 10.16016/j.1000-5404.201508073.

CHARAN J, KANTHARIA N D. How to calculate sample size in animal studies?[J]. J Pharmacol Pharmacother, 2013, 4(4): 303-306. DOI: 10.4103/0976-500X.119726.

GARCIA J H, WAGNER S, LIU K F, et al. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation[J]. Stroke, 1995, 26(4): 627-634.

SUGAWARA T, AYER R, JADHAV V, et al. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model[J]. J Neurosci Methods, 2008, 167(2): 327-334. DOI: 10.1016/j.jneumeth.2007.08.004.

LEE J Y, HE Y, SAGHER O, et al. Activated autophagy pathway in experimental subarachnoid hemorrhage[J]. Brain Res, 2009, 1287: 126-135. DOI: 10.1016/j.brainres.2009.06.028.

BELL R D, WINKLER E A, SINGH I, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A[J ] . Nature, 2012, 485(7399): 512-516. DOI: 10.1038/nature11087.

Jiang Y, Sun X, Gui L, et al. Correlation between APOE -491AA promoter in epsilon 4 carriers and clinical deterioration in early stage of traumatic brain injury[J]. J Neurotrauma, 2007, 24(12): 1802-1810. DOI: 10.1089/neu.2007.0299.

刘杰什, 秦兴虎, 曹芳, 等. APOE基因亚型对创伤性脑损伤后COG1410早期神经保护作用的影响[J].第三军医大学学报, 2015, 37(10): 990-995. DOI: 10.16016/j.1000-5404.201502003.

LIU J S, QIN X H, CAO F, et al.Effect of apolipoprotein E genotypes on early neuroprotective function of COG1410 after traumatic brain injury[J]. J Third Mil Med Univ, 2015, 37 (10): 990-995. DOI: 10.16016/j.1000-5404.201502003.

JIANG Y, BRODY D L. Administration of COG1410 reduces axonal amyloid precursor protein immunoreactivity and microglial activation after controlled cortical impact in mice[J]. J Neurotrauma, 2012, 29(13): 2332-2341. DOI: 10.1089/neu.2012.2362.

秦兴虎, 游红, 郐莉, 等.载脂蛋白E拟肽对创伤性脑损伤后脑组织TNF-α表达和脑水肿的影响及意义[J].中华神经医学杂志, 2016, 15(1): 35-40. DOI: 10.3760/cma.j.issn.1671-8925.2016.01.008.

QIN X H, YOU H, KUAI L, et al.Effect of apolipoprotein E peptide on tumor necrosis factor α in brain tissues and its significance after traumatic brain injury[J].Chin J Neuromed, 2016, 15(1): 35-40. DOI: 10.3760/cma.j.issn.1671-8925.2016.01.008.

PANG J, CHEN Y, KUAI L, et al. Inhibition of blood-brain barrier disruption by an apolipoprotein E-mimetic peptide ameliorates early brain injury in experimental subarachnoid hemorrhage[J]. Transl Stroke Res, 2017, 8(3): 257-272.DOI: 10.1007/s12975-016-0507-1.

WU Y, PANG J W, PENG J H,et al. An apoE-derived mimic peptide, COG1410, alleviates early brain injury via reducing apoptosis and neuroinflammation in a mouse model of subarachnoid hemorrhage[J]. Neurosci Lett, 2016, 627: 92-99. DOI: 10.1016/j.neulet.2016.05.058.

GALLUZZI L, BRAVO-SAN PEDRO J M, BLOMGREN K, et al. Autophagy in acute brain injury[J]. Nat Rev Neurosci, 2016, 17(8): 467-484. DOI: 10.1038/nrn.2016.51.

JING C H, WANG L, LIU PP, et al. Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage[J ] . Neuroscience, 2012, 213: 144-153. DOI: 10.1016/j.neuroscience.2012.03.055.

CHEN J, WANG L, WU C, et al. Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage[J]. J Pineal Res, 2014, 56(1): 12-19. DOI: 10.1111/jpi.12086.

SHAO A, WANG Z, WU H, et al. Enhancement of Autophagy by Histone Deacetylase Inhibitor Trichostatin A Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats[J]. Mol Neurobiol, 2016, 53(1): 18-27. DOI: 10.1007/s12035-014-8986-0.

ZHAO H, JI Z, TANG D, et al. Role of autophagy in early brain injury after subarachnoid hemorrhage in rats[J]. Mol Biol Rep, 2013, 40(2): 819-827.

戴旭芳, 秦利燕, 连继勤.白藜芦醇对孤独症大鼠病症行为的改善作用[J].第三军医大学学报, 2017, 39(13): 1360-1365.DOI: 10.16016/j.1000-5404.201703153.

DAI X F, QIN L Y, LIAN J Q.Resveratrol improves autistic behaviors in rat model[J].J Third Mil Med Univ, 2017, 39 (13): 1360-1365. DOI: 10.16016/j.1000-5404.201703153.

LIANG M H, CHUANG DM. Regulation and function of glycogen synthase kinase-3 isoforms in neuronal survival[J]. J Biol Chem, 2007, 282(6): 3904-3917. DOI: 10.1074/jbc.M605178200.

COLLINO M, THIEMERMANNC, MASTROCOLA R, et al. Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus[J]. Shock, 2008, 30(3): 299-307. DOI: 10.1097/SHK.0b013e318164e762.

HETMAN M, CAVANAUGH J E, KIMELMAN D, et al. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal[J]. J Neurosci, 2000, 20(7): 2567-2574.

ZHOU X, ZHOU J, LI X, et al. GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury[J]. Biochem Biophys Res Commun, 2011, 411(2): 271-275. DOI: 10.1016/j.bbrc.2011.06.117.

SHANG Y, WU Y, YAO S, et al. Protective effect of erythropoietin against ketamine-induced apoptosis in cultured rat cortical neurons: involvement of PI3K/Akt and GSK-3 beta pathway[J]. Apoptosis, 2007, 12(12): 2187-2195. DOI: 10.1007/s10495-007-0141-1.

汪庭龙, 吴林, 胡玉英, 等.蛋白激酶B信号通路的干预在慢性脑低灌注大鼠中的作用及对海马细胞凋亡的影响[J].中华老年心脑血管病杂志, 2016, 18(7): 744-747. DOI: 10.3969/j.issn.1009-0126.2016.07.019.

WANG T L, WU L, HU Y Y, et al.Effect of Akt/GSK3β signaling pathway on chronic cerebral hypoperfusion and hippocampal cellular apoptosis in rats[J]. Chin J Geriatr Heart Brain Vessel Dis, 2016, 18(7): 744-747. DOI: 10.3969/j.issn.1009-0126.2016.07.019.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

自噬通过降解铁蛋白促进神经元铁死亡参与蛛网膜下腔出血后早期脑损伤

蛛网膜下腔出血后早期脑损伤中ROS和PDGFR活化的研究

依布硒林减轻DMT1诱导的铁死亡在实验性大鼠蛛网膜下腔出血中的研究

吉西他滨诱导膀胱癌T24细胞自噬的实验研究

液态氟碳纳米粒在大鼠蛛网膜下腔出血中对低氧诱导因子1α的抑制作用