Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

Junjun GENG; Jun TANG; Lili WANG; Qiang TAN; Jianbo ZHANG; Bo ZHANG; Ling WANG; Linjie WEI; Zhi CHEN; Gang ZHU

doi:10.16016/j.1000-5404.201909112

您当前的位置：

首页 >

文章列表页 >

Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

Basic Medicine | 更新时间：2026-01-09

- Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats
- Journal of Third Military Medical University Vol. 41, Issue 22, Pages: 2137-2145(2019)
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)附属第一医院神经外科
  2.710032 西安，空军军医大学附属第一医院急诊科
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(81601356);the General Program of National Natural Science Foundation of China(81571116);the Innovation Military Medical Science and Technology(SWH2017YBXM-19)
- DOI：10.16016/j.1000-5404.201909112
  CLC： R-322;R392.32;R722.151
- Received：15 September 2019，
  
  Revised：2019-10-11，
  
  Published：30 November 2019
- 稿件说明：
移动端阅览
Junjun GENG, Jun TANG, Lili WANG, et al. Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats[J]. Journal of Third Military Medical University, 2019, 41(22): 2137-2145.
DOI：

Junjun GENG, Jun TANG, Lili WANG, et al. Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats[J]. Journal of Third Military Medical University, 2019, 41(22): 2137-2145. DOI： 10.16016/j.1000-5404.201909112.

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.

Methods

GMH 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.

Results

The 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.

Conclusion

GMH 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.

关键词

Keywords

references

BALLABH P. Intraventricular hemorrhage in premature infants: mechanism of disease[J]. Pediatr Res, 2010, 67(1): 1-8. DOI: 10.1203/PDR.0b013e3181c1b176.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

LIPINA R, REGULI S, NOVÁCKOVÁ 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.

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.

YASUI M. Roles of aquaporins in the central nervous system[J]. Masui, 2008, 57(Suppl): S28-S33.

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.

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.

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.

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.

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.

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.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Application of early continuous lumbar cerebrospinal fluid drainage in children after resection of posterior cranial fossa tumors

Loss of liver X receptor β in astrocytes leads to defects in early postnatal hippocampal neurogenesis in mice

Effects of hippocampal PGC-1α on depression-like behaviors and number of astrocytes in hippocampal subregions in mice

Risk factors of chronic hydrocephalus after operation of aneurysmal subarachnoid hemorrhage

BAMBI inhibits apoptosis in glutamate induced neurons and astrocytes in spinal dorsal horn of rats via regulating autophagy

Related Author

Wenyuan JI

Ping LIANG

Lusheng LI

Xuan ZHAI

Yudong ZHOU

Keyi LYU

Yi LUO

Xin LI

Related Institution

Department of Neurosurgery, Key Laboratory of Child Development and Disorders of Ministry of Education, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University

Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest University

Department of Military Cognitive Psychology, Faculty of Medical Psychology, Army Medical University (Third Military Medical University)

Department of Histology and Embryology, College of Basic Medical Sciences, Chongqing Medical University

Laboratory of Stem Cells and Tissue Engineering, College of Basic Medical Sciences, Chongqing Medical University

⁰