Skip to main content
SpringerLink
Log in

Aquaporin4 Knockout Aggravates Early Brain Injury Following Subarachnoid Hemorrhage Through Impairment of the Glymphatic System in Rat Brain

  • Chapter
  • First Online:
Subarachnoid Hemorrhage

Part of the book series: Acta Neurochirurgica Supplement ((NEUROCHIRURGICA,volume 127))

Abstract

Background: It is reported that the expression of aquaporin4 (AQP4) in the brain is increased and leads to the brain edema after subarachnoid hemorrhage (SAH). In this study, by using AQP4 knockout rat model, the opposite role of AQP4 in early brain injury following SAH through modulation of interstitial fluid (ISF) transportation in the brain glymphatic system had been explored.

Methods: The SAH model was established using endovascular perforation method, the AQP4 knockout rat model was generated using TALENs (transcription activator-like (TAL) effector nucleases) technique. The animals were randomly divided into four groups: sham (n = 16), AQP4−/−sham (n = 16), SAH (n = 24), and AQP4−/−SAH groups (n = 27). The roles of AQP4 in the brain water content and neurological function were detected. In addition, immunohistochemistry and Nissl staining were applied to observe the effects of AQP4 on the blood–brain barrier (BBB) integrity and the loss of neurons in the hippocampus. To explore the potential mechanism of these effects, the distribution of Gd-DTPA (interstitial fluid indicator) injected from cisterna magna was evaluated with MRI.

Results: Following SAH, AQP4 knockout could significantly increase the water content in the whole brain and aggravate the neurological deficits. Furthermore, the loss of neuron and BBB disruption in hippocampus were also exacerbated. The MRI results indicated that the ISF transportation in the glymphatic system of AQP4 deficit rat was significantly injured.

Conclusion: AQP4 facilitates the ISF transportation in the brain to eliminate the toxic factors; AQP4 knockout will aggravate the early brain injury following SAH through impairment of the glymphatic system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Li J, Chen J, Mo H, Chen J, Qian C, Yan F, Gu C, Hu Q, Wang L, Chen G. Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury after subarachnoid hemorrhage. Mol Neurobiol. 2016;53:2668–78.

    Article  CAS  Google Scholar 

  2. Yuan J, Liu W, Zhu H, Zhang X, Feng Y, Chen Y, Feng H, Lin J. Curcumin attenuates blood-brain barrier disruption after subarachnoid hemorrhage in mice. J Surg Res. 2017;207:85–91.

    Article  CAS  Google Scholar 

  3. Plog BA, Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol. 2018;13:379–94.

    Article  CAS  Google Scholar 

  4. Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40:2583–99.

    Article  CAS  Google Scholar 

  5. Badaut J, Brunet JF, Grollimund L, Hamou MF, Magistretti PJ, Villemure JG, Regli L. Aquaporin 1 and aquaporin 4 expression in human brain after subarachnoid hemorrhage and in peritumoral tissue. Acta Neurochir Suppl. 2003;86:495–8.

    CAS  PubMed  Google Scholar 

  6. Yang X, Chen C, Hu Q, Yan J, Zhou C. Gamma-secretase inhibitor (GSI1) attenuates morphological cerebral vasospasm in 24h after experimental subarachnoid hemorrhage in rats. Neurosci Lett. 2010;469:385–90.

    Article  CAS  Google Scholar 

  7. Yan JH, Khatibi NH, Han HB, Hu Q, Chen CH, Li L, Yang XM, Zhou CM. p53-induced uncoupling expression of aquaporin-4 and inwardly rectifying K+ 4.1 channels in cytotoxic edema after subarachnoid hemorrhage. CNS Neurosci Ther. 2012;18:334–42.

    Article  CAS  Google Scholar 

  8. Tesson L, Usal C, Menoret S, Leung E, Niles BJ, Remy S, Santiago Y, Vincent AI, Meng X, Zhang L, Gregory PD, Anegon I, Cost GJ. Knockout rats generated by embryo microinjection of TALENs. Nat Biotechnol. 2011;29:695–6.

    Article  CAS  Google Scholar 

  9. Sung YH, Jin Y, Kim S, Lee HW. Generation of knockout mice using engineered nucleases. Methods. 2014;69:85–93.

    Article  CAS  Google Scholar 

  10. Duris K, Manaenko A, Suzuki H, Rolland W, Tang J, Zhang JH. Sampling of CSF via the cisterna magna and blood collection via the heart affects brain water content in a rat SAH model. Transl Stroke Res. 2011;2:232–7.

    Article  CAS  Google Scholar 

  11. Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995;26:627–34. discussion 635.

    Article  CAS  Google Scholar 

  12. Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, Touze E, Vivien D, Gauberti M. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014;45:3092–6.

    Article  CAS  Google Scholar 

  13. Zhou C, Yamaguchi M, Colohan AR, Zhang JH. Role of p53 and apoptosis in cerebral vasospasm after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2005;25:572–82.

    Article  CAS  Google Scholar 

  14. Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol. 2012;97:14–37.

    Article  Google Scholar 

  15. Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res. 2013;4:432–46.

    Article  Google Scholar 

  16. Goulay R, Flament J, Gauberti M, Naveau M, Pasquet N, Gakuba C, Emery E, Hantraye P, Vivien D, Aron-Badin R, Gaberel T. Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke. 2017;48:2301–5.

    Article  Google Scholar 

  17. Luo C, Yao X, Li J, He B, Liu Q, Ren H, Liang F, Li M, Lin H, Peng J, Yuan TF, Pei Z, Su H. Paravascular pathways contribute to vasculitis and neuroinflammation after subarachnoid hemorrhage independently of glymphatic control. Cell Death Dis. 2016;7:e2160.

    Article  CAS  Google Scholar 

  18. Morris AW, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016;131:725–36.

    Article  CAS  Google Scholar 

  19. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212:991–9.

    Article  CAS  Google Scholar 

  20. Mestre H, Kostrikov S, Mehta RI, Nedergaard M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin Sci (Lond). 2017;131:2257–74.

    Article  CAS  Google Scholar 

  21. Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E, Regan S, Kasper T, Peng S, Ding F, Benveniste H, Nedergaard M, Deane R. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2016;93:215–25.

    Article  CAS  Google Scholar 

  22. Arbel-Ornath M, Hudry E, Eikermann-Haerter K, Hou S, Gregory JL, Zhao L, Betensky RA, Frosch MP, Greenberg SM, Bacskai BJ. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models. Acta Neuropathol. 2013;126:353–64.

    Article  CAS  Google Scholar 

  23. Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013;14:265–77.

    Article  CAS  Google Scholar 

  24. Vindedal GF, Thoren AE, Jensen V, Klungland A, Zhang Y, Holtzman MJ, Ottersen OP, Nagelhus EA. Removal of aquaporin-4 from glial and ependymal membranes causes brain water accumulation. Mol Cell Neurosci. 2016;77:47–52.

    Article  CAS  Google Scholar 

  25. Li X, Liu H, Yang Y. Magnesium sulfate attenuates brain edema by lowering AQP4 expression and inhibits glia-mediated neuroinflammation in a rodent model of eclampsia. Behav Brain Res. 2017;364:403–12.

    Article  Google Scholar 

  26. Han H, Shi C, Fu Y, Zuo L, Lee K, He Q, Han H. A novel MRI tracer-based method for measuring water diffusion in the extracellular space of the rat brain. IEEE J Biomed Health Inform. 2014;18:978–83.

    Article  Google Scholar 

  27. Nicholson C, Phillips JM. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol. 1981;321:225–57.

    Article  CAS  Google Scholar 

  28. Nicholson C. Quantitative analysis of extracellular space using the method of TMA+ iontophoresis and the issue of TMA+ uptake. Can J Physiol Pharmacol. 1992;70(Suppl):S314–22.

    Article  CAS  Google Scholar 

  29. Xiao F, Nicholson C, Hrabe J, Hrabetova S. Diffusion of flexible random-coil dextran polymers measured in anisotropic brain extracellular space by integrative optical imaging. Biophys J. 2008;95:1382–92.

    Article  CAS  Google Scholar 

  30. Ten Kate M, Visser PJ, Bakardjian H, Barkhof F, Sikkes SAM, van der Flier WM, Scheltens P, Hampel H, Habert MO, Dubois B, Tijms BM. Gray matter network disruptions and regional amyloid beta in cognitively normal adults. Front Aging Neurosci. 2018;10:67.

    Article  Google Scholar 

  31. Blixt J, Gunnarson E, Wanecek M. Erythropoietin attenuates the brain edema response after experimental traumatic brain injury. J Neurotrauma. 2018;35:671–80.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 31471028) and the interdisciplinary medicine Seed Fund of Peking University (Grant No. BMU2018MC001).

Conflict of Interest: The authors declare that they have no conflict of interest.

Author information

Author notes

  1. $E. Liu and Linlin Sun contributed equally to this study.

Authors and Affiliations

  1. Department of Anatomy and Histology, School of Basic Medical Sciences, Peking University, Beijing, China

    E. Liu, Linlin Sun, Yixuan Zhang & Junhao Yan

  2. Beijing Key Lab of Magnetic Resonance Imaging Technology, Beijing, China

    Aibo Wang & Junhao Yan

Authors
  1. E. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linlin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yixuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aibo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junhao Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junhao Yan .

Editor information

Editors and Affiliations

  1. Department of Anethesiology, Loma Linda University Medical Center, Loma Linda, CA, USA

    Robert D. Martin

  2. Department of Neurosurgery, Loma Linda University Medical Center, Loma Linda, CA, USA

    Warren Boling

  3. Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, China

    Gang Chen

  4. Department of Anesthesiology and Physiology, Loma Linda University Medical Center, Loma Linda, CA, USA

    John H. Zhang

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Liu, E., Sun, L., Zhang, Y., Wang, A., Yan, J. (2020). Aquaporin4 Knockout Aggravates Early Brain Injury Following Subarachnoid Hemorrhage Through Impairment of the Glymphatic System in Rat Brain. In: Martin, R., Boling, W., Chen, G., Zhang, J. (eds) Subarachnoid Hemorrhage. Acta Neurochirurgica Supplement, vol 127. Springer, Cham. https://doi.org/10.1007/978-3-030-04615-6_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-04615-6_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-04614-9

  • Online ISBN: 978-3-030-04615-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation