[1]耿军军,唐俊,王莉莉,等.抑制补体C3/C3aR信号可改善新生大鼠脑生发基质出血后脑积水[J].第三军医大学学报,2019,41(22):1237-1245.
 GENG Junjun,TANG Jun,WANG Lili,et al.Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats [J].J Third Mil Med Univ,2019,41(22):1237-1245.
点击复制

抑制补体C3/C3aR信号可改善新生大鼠脑生发基质出血后脑积水(/HTML )
分享到:

《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第22期
页码:
1237-1245
栏目:
基础医学
出版日期:
2019-11-30

文章信息/Info

Title:
Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats 
作者:
耿军军唐俊王莉莉谭强张建波张波王玲魏林节陈志朱刚
陆军军医大学(第三军医大学)附属第一医院神经外科;空军军医大学附属第一医院急诊科
Author(s):
GENG Junjun TANG Jun WANG Lili TAN Qiang ZHANG Jianbo ZHANG Bo WANG Ling WEI Linjie CHEN Zhi ZHU Gang

Department of Neurosurgery, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038; Department of Emergency, First Affiliated Hospital, Air Force Medical University, Xi’an, Shaanxi Province, 710032, China

关键词:
生发基质出血脑积水C3/C3aR信号星形胶质细胞小胶质细胞水通道蛋白4大鼠新生
Keywords:
germinal matrix hemorrhage hydrocephalus C3/C3aR astrocytes microglias aquaporin 4 rats newborn
分类号:
R-322; R392.32; R722.151
文献标志码:
A
摘要:

目的 研究补体C3/C3aR信号介导的小胶质细胞-星型胶质细胞交互作用对新生大鼠脑生发基质出血(germinal matrix hemorrhage,GMH)后脑积水的影响。方法 检测胶原酶(Ⅶ-S型)诱导新生大鼠GMH后脑室周围C3和C3aR的表达。给予GMH大鼠C3aR拮抗剂(complement C3 receptor antagonist,C3aRA)处理,观察C3aRA对大鼠脑积水(MRI检查)、学习记忆功能(水迷宫实验)和炎症反应(IL-1β、IL-6、TNF-α、TGF-β1和水通道蛋白4)的影响。结果GMH后脑室周围补体C3和C3aR表达上调,炎症因子IL-1β、IL-6、TNF-α、TGF-β1表达增加,星形胶质细胞表面的水通道蛋白4异位表达且表达增加,脑室扩张,脑皮质和海马受压,大鼠学习记忆功能下降。阻断C3/C3aR信号后,相应C3、C3aR表达减低,炎症因子分泌减少,脑室扩张程度及皮层/海马受压减轻,大鼠神经功能明显改善。结论 GMH后星形胶质细胞上调并释放C3, C3与小胶质细胞表面的C3aR结合促进炎症反应,加重脑积水。星形胶质细胞表面水通道蛋白4的异位表达可能对GMH后脑积水产生起重要作用。

Abstract:
Objective To investigate the effect of astrocyte-microglia crosstalk mediated by complement C3/C3aR signaling on hydrocephalus after germinal matrix hemorrhage (GMH) in newborn rats. MethodsGMH was induced in post-natal day 7 SD rats by collagenase Ⅶ-S injection into the ganglionic eminence. We detected the changes in the expression of periventricular C3 and C3aR over time after GMH, and observed the effect of intraperitoneal injection of C3aRA (a selective C3aR antagonist) on hydrocephalus using magnetic resonance imaging (MRI). The learning and memory functions of the rats were tested after the treatment using Morris water maze test, and  the expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and aquaporin 4 in the brain tissues were detected using Western blotting at different time points after GMH. ResultsThe neonatal rats with GMH showed significantly up-regulated expression of C3 and C3aR around the cerebral ventricles and increased expression of IL-1β, IL-6, TNF-α and TGF-β1 in the brain, presenting also with obvious lateral ventricle dilation, compression of the cortex and hippocampus, and impairment of the learning and memory functions. Treatment of the rats with C3aRA obviously decreased C3 and C3aR expression, alleviated hydrocephalus, improved the neurological deficits, and reduced the expression of the inflammatory factors in the brain. GMH caused obvious ectopic expression of aquaporins 4 and increased its expression level on the astrocytes, and C3aRA treatment significantly improved the abnormal expression of aquaporins 4. ConclusionGMH causes the astrocytes to up-regulate and release C3, which binds to C3aR on the microglia to promote inflammation and aggravate hydrocephalus. The ectopic expression of aquaporin 4 in astrocytes may play an important role in the occurrence of hydrocephalus following GMH.
 

参考文献/References:

 
[1]BALLABH P. Intraventricular hemorrhage in premature infants:  mechanism of disease[J]. Pediatr Res, 2010, 67(1):  1-8. DOI: 10.1203/PDR.0b013e3181c1b176. 
[2]ELLENBOGEN J R, WAQAR M, PETTORINI B. Management of post-haemorrhagic hydrocephalus in premature infants[J]. J Clin Neurosci, 2016, 31:  30-34. DOI: 10.1016/j.jocn.2016.02.026. 
[3]WU Y, GREEN N L, WRENSCH M R, et al. Ventriculoperitoneal shunt complications in California:  1990 to 2000[J]. Neurosurgery, 2007, 61(3):  557-562; discussion 562-3. DOI: 10.1227/01.NEU.0000290903.07943.AF. 
[4]KARIMY J K, ZHANG J W, KURLAND D B, et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus[J]. Nat Med, 2017, 23(8):  997-1003. DOI: 10.1038/nm.4361. 
[5]GIMSA U, MITCHISON N A, BRUNNER-WEINZIERL M C. Immune privilege as an intrinsic CNS property:  astrocytes protect the CNS against T-cell-mediated neuroinflammation[J]. Mediators Inflamm, 2013, 2013:  320519. DOI: 10.1155/2013/320519.
[6]WANG C, YAN M Y, JIANG H, et al. Mechanism of aquaporin 4 (AQP4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin[J]. Life Sci, 2018, 193:  270-281. DOI: 10.1016/j.lfs.2017.10.021. 
[7]YANG S X, NAKAMURA T, HUA Y, et al. The role of complement C3 in intracerebral hemorrhage-induced brain injury[J]. J Cereb Blood Flow Metab, 2006, 26(12):  1490-1495. DOI: 10.1038/sj.jcbfm.9600305. 
[8]SEELE J, KIRSCHFINK M, DJUKIC M, et al. Cisterno-lumbar gradient of complement fractions in geriatric patients with suspected normal pressure hydrocephalus[J]. Clin Chim Acta, 2018, 486:  1-7. DOI: 10.1016/j.cca.2018.07.008. 
[9]LIAN H, LITVINCHUK A, CHIANG A C, et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease[J]. J Neurosci, 2016, 36(2):  577-589. DOI: 10.1523/JNEUROSCI.2117-15.2016. 
[10]LIDDELOW S A, GUTTENPLAN K A, CLARKE L E, et al. Neurotoxic reactive astrocytes are induced by activated microglia[J]. Nature, 2017, 541(7638):  481-487. DOI: 10.1038/nature21029. 
[11]TANG J, CHEN Q W, GUO J, et al. Minocycline attenuates neonatal germinal-matrix-hemorrhage-induced neuroinflammation and brain edema by activating cannabinoid receptor 2[J]. Mol Neurobiol, 2016, 53(3):  1935-1948. DOI: 10.1007/s12035-015-9154-x. 
[12]RYNKOWSKI M A, KIM G H, GARRETT M C, et al. C3a receptor antagonist attenuates brain injury after intracerebral hemorrhage[J]. J Cereb Blood Flow Metab, 2009, 29(1):  98-107. DOI: 10.1038/jcbfm.2008.95. 
[13]OKAUCHI M, HUA Y, KEEP R F, et al. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats[J]. Stroke, 2009, 40(5):  1858-1863. DOI: 10.1161/STROKEAHA.108.535765. 
[14]KAHLE K T, KULKARNI A V, LIMBRICK D D Jr, et al. Hydrocephalus in children[J]. Lancet, 2016, 387(10020):  788-799. DOI: 10.1016/S0140-6736(15)60694-8. 
[15]TULLY H M, DOBYNS W B. Infantile hydrocephalus:  a review of epidemiology, classification and causes[J]. Eur J Med Genet, 2014, 57(8):  359-368. DOI: 10.1016/j.ejmg.2014.06.002. 
[16]GIMSA U, MITCHISON N A, BRUNNER-WEINZIERL M C. Immune privilege as an intrinsic CNS property:  astrocytes protect the CNS against T-cell-mediated neuroinflammation[J]. Mediators Inflamm, 2013, 2013:  320519. DOI: 10.1155/2013/320519. 
[17]FUKUDA S, ABEMATSU M, MORI H, et al. Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-smad signaling in neural stem cells[J]. Mol Cell Biol, 2007, 27(13):  4931-4937. DOI:  10.1128/MCB.02435-06. 
[18]LIPINA R, REGULI S, NOVCKOV L, et al. Relation between TGF-beta 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus[J]. Childs Nerv Syst, 2010, 26(3):  333-341. DOI: 10.1007/s00381-009-1011-7. 
[19]YANG S X, NAKAMURA T, HUA Y, et al. The role of complement C3 in intracerebral hemorrhage-induced brain injury[J]. J Cereb Blood Flow Metab, 2006, 26(12):  1490-1495. DOI: 10.1038/sj.jcbfm.9600305. 
[20]YASUI M. Roles of aquaporins in the central nervous system[J]. Masui, 2008, 57(Suppl):  S28-S33. 
[21]MCALLISTER J P 2nd, MILLER J M. Aquaporin 4 and hydrocephalus[J]. J Neurosurg, 2006, 105(6 Suppl):  457-458. DOI: 10.3171/ped.2006.105.6.457. 
[22]ASAI H, KAKITA H, AOYAMA M, et al. Diclofenac enhances proinflammatory cytokine-induced aquaporin-4 expression in cultured astrocyte[J]. Cell Mol Neurobiol, 2013, 33(3):  393-400. DOI: 10.1007/s10571-013-9905-z. 
[23]WANG C, YAN M Y, JIANG H, et al. Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin[J]. Life Sci, 2018, 193:  270-281. DOI: 10.1016/j.lfs.2017.10.021. 
[24]FUKUDA A M, BADAUT J. Aquaporin 4:  a player in cerebral edema and neuroinflammation[J]. J Neuroinflamm, 2012, 9:  279. DOI: 10.1186/1742-2094-9-279. 
[25]TOURDIAS T, DRAGONU I, FUSHIMI Y, et al. Aquaporin 4 correlates with apparent diffusion coefficient and hydrocephalus severity in the rat brain:  a combined MRI-histological study[J]. Neuroimage, 2009, 47(2):  659-666. DOI: 10.1016/j.neuroimage.2009.04.070. 
[26]DING Y, ZHANG T Y, WU G Y, et al. Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage[J]. Exp Neurol, 2019, 320:  113003. DOI: 10.1016/j.expneurol.2019.113003. 
 

相似文献/References:

[1]宫国旗,孟辉,夏永智,等.大鼠实验性脑室出血后慢性脑积水动物模型的建立及病理学观察[J].第三军医大学学报,2008,30(10):969.
 GONG Guo-qi,MENG Hui,XIA Yong-zhi,et al.Experimental chronic hydrocephalus after intraventricular hemorrhage in rats: establishment of animal model and pathological observation[J].J Third Mil Med Univ,2008,30(22):969.
[2]钟东,支兴刚,唐文渊.单纯神经内窥镜手术治疗三脑室内囊性颅咽管瘤效果[J].第三军医大学学报,2006,28(06):556.
[3]宫国旗,孟辉,冯华.铁离子在大鼠实验性慢性脑积水发生中的作用[J].第三军医大学学报,2008,30(23):2172.
 GONG Guo-qi,MENG Hui,FENG Hua.Role of iron ion in development of hydrocephalus in rats[J].J Third Mil Med Univ,2008,30(22):2172.
[4]翟瑄,梁平,夏佐中,等.可调压式分流管治疗小儿脑积水的临床观察[J].第三军医大学学报,2011,33(24):2614.
 Zhai Xuan,Liang Ping,Xia Zuozhong,et al.Clinical efficiency of programmable shunt valve in treatment of hydrocephalus in children[J].J Third Mil Med Univ,2011,33(22):2614.
[5]纪文元,梁平,李禄生,等.早期腰大池持续脑脊液外引流术在儿童后颅窝肿瘤切除术中的应用[J].第三军医大学学报,2018,40(05):454.
 JI Wenyuan,LIANG Ping,LI Lusheng,et al.Application of early continuous lumbar cerebrospinal fluid drainage in children after resection of posterior cranial fossa tumors[J].J Third Mil Med Univ,2018,40(22):454.

更新日期/Last Update: 2019-11-21