Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate) Receptor Reduces Acute Blood–Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) is thought to cause acute brain injury, but the role remains poorly understood in subarachnoid hemorrhage (SAH). This study was conducted to evaluate if AMPAR activation induces acute blood–brain barrier (BBB) disruption after SAH. C57BL/6 male adult mice (n = 117) underwent sham or filament perforation SAH modeling, followed by a random intraperitoneal injection of vehicle or two dosages (1 mg/kg or 3 mg/kg) of a selective noncompetitive AMPAR antagonist perampanel (PER) at 30 min post-modeling. The effects were evaluated by mortality, neurological scores, and brain water content at 24–48 h and video electroencephalogram monitoring, immunostaining, and Western blotting at 24 h post-SAH. PER significantly suppressed post-SAH neurological impairments, brain edema, and BBB disruption. SAH developed epileptiform spikes without obvious convulsion, which were also inhibited by PER. Western blotting showed that the expression of AMPAR subunits GluA1 and GluA2 was unchanged after SAH, but they were significantly activated after SAH. PER prevented post-SAH activation of GluA1/2, associated with the suppression of post-SAH induction of tenascin‐C, a causative mediator of post-SAH BBB disruption. Meanwhile, an intracerebroventricular injection of a subtype-selective GluA1/2 agonist augmented the activation of GluA1/2 and the induction of tenascin-C in brain capillary endothelial cells and aggravated post-SAH BBB disruption without increases in epileptiform spikes. Neurological impairments and brain edema were not correlated with the occurrence of epileptiform spikes. This study first showed that AMPAR plays an important role in the development of post-SAH BBB disruption and can be a novel therapeutic target against it.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Suzuki H, Shiba M, Nakatsuka Y, Nakano F, Nishikawa H. Higher cerebrospinal fluid pH may contribute to the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Transl Stroke Res. 2017;8:165–73.

    Article  CAS  PubMed  Google Scholar 

  2. Suzuki H. What is early brain injury? Transl Stroke Res. 2015;6:1–3.

    Article  PubMed  Google Scholar 

  3. Suzuki H, Kanamaru H, Kawakita F, Asada R, Fujimoto M, Shiba M. Cerebrovascular pathophysiology of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Histol Histopathol. 2020:18253. https://doi.org/10.14670/HH-18-253.

  4. Kim JA, Rosenthal ES, Biswal S, Zafar S, Shenoy AV, O’Connor KL, Bechek SC, Valdery Moura J, Shafi MM, Patel AB, Cash SS, Westover MB. Epileptiform abnormalities predict delayed cerebral ischemia in subarachnoid hemorrhage. Clin Neurophysiol. 2017;128:1091–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Löscher W. Epilepsy and alterations of the blood-brain barrier: cause or consequence of epileptic seizures or both? Handb Exp Pharmacol. 2020. https://doi.org/10.1007/164_2020_406.

  6. Kett-White R, Hutchinson PJ, Al-Rawi PG, Gupta AK, Pickard JD, Kirkpatrick PJ. Adverse cerebral events detected after subarachnoid hemorrhage using brain oxygen and microdialysis probes. Neurosurgery. 2002;50:1213–22.

    PubMed  Google Scholar 

  7. Zhang C, Jiang M, Wang WQ, Zhao SJ, Yin YX, Mi QJ, Yang MF, Song YQ, Sun BL, Zhang ZY. Selective mGluR1 negative allosteric modulator reduces blood-brain barrier permeability and cerebral edema after experimental subarachnoid hemorrhage. Transl Stroke Res. 2020;11:799–811.

    Article  CAS  PubMed  Google Scholar 

  8. Scharfman HE. The neurobiology of epilepsy. Curr Neurol Neurosci Rep. 2007;7:348–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Lv JM, Guo XM, Chen B, Lei Q, Pan YJ, Yang Q. The noncompetitive AMPAR antagonist perampanel abrogates brain endothelial cell permeability in response to ischemia: Involvement of claudin-5. Cell Mol Neurobiol. 2016;36:745–53.

    Article  CAS  PubMed  Google Scholar 

  10. Liu L, Fujimoto M, Kawakita F, Nakano F, Imanaka-Yoshida K, Yoshida T, Suzuki H. Anti-vascular endothelial growth factor treatment suppresses early brain injury after subarachnoid hemorrhage in mice. Mol Neurobiol. 2016;53:4529–38.

    Article  CAS  PubMed  Google Scholar 

  11. Liu L, Kawakita F, Fujimoto M, Nakano F, Imanaka-Yoshida K, Yoshida T, Suzuki H. Role of periostin in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2017;48:1108–11.

    Article  PubMed  Google Scholar 

  12. Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, Yoshida T, Suzuki H. Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice. J Neurosurg. 2016;124:1693–702.

    Article  CAS  PubMed  Google Scholar 

  13. Suzuki H, Fujimoto M, Kawakita F, Liu L, Nakatsuka Y, Nakano F, Nishikawa H, Okada T, Kanamaru H, Imanaka-Yoshida K, Yoshida T, Shiba M. Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: findings from basic and clinical studies. J Neurosci Res. 2020;98:42–56.

    Article  CAS  PubMed  Google Scholar 

  14. Nakajima M, Suda S, Sowa K, Sakamoto Y, Nito C, Nishiyama Y, Aoki J, Ueda M, Yokobori S, Yamada M, Yokota H, Okada T, Kimura K. AMPA receptor antagonist perampanel ameliorates post-stroke functional and cognitive impairments. Neuroscience. 2018;386:256–64.

    Article  CAS  PubMed  Google Scholar 

  15. Altay O, Suzuki H, Hasegawa Y, Caner B, Krafft PR, Fujii M, Tang J, Zhang JH. Isoflurane attenuates blood-brain barrier disruption in ipsilateral hemisphere after subarachnoid hemorrhage in mice. Stroke. 2012;43:2513–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Russmann V, Salvamoser JD, Rettenbeck ML, Komori T, Potschka H. Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy. Epilepsia. 2016;57:638–47.

    Article  CAS  PubMed  Google Scholar 

  17. Bjerrum EJ, Kristensen AS, Pickering DS, Greenwood JR, Nielsen B, Liljefors T, Schousboe A, Bräuner-Osborne H, Madsen U. Design, synthesis, and pharmacology of a highly subtype-selective GluR1/2 agonist, (RS)-2-amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic acid (Cl-HIBO). J Med Chem. 2003;46:2246–9.

    Article  CAS  PubMed  Google Scholar 

  18. You JC, Muralidharan K, Park JW, Petrof I, Pyfer MS, Corbett BF, LaFrancois JJ, Zheng Y, Zhang X, Mohila CA, Yoshor D, Rissman RA, Nestler EJ, Scharfman HE, Chin J. Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits. Nat Med. 2017;23:1377–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Anjum SMM, Käufer C, Hopfengärtner R, Waltl I, Bröer S, Löscher W. Automated quantification of EEG spikes and spike clusters as a new read out in Theiler’s virus mouse model of encephalitis-induced epilepsy. Epilepsy Behav. 2018;88:189–204.

    Article  PubMed  Google Scholar 

  20. Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods. 2008;167:327–34.

    Article  PubMed  Google Scholar 

  21. Nakano F, Kawakita F, Liu L, Nakatsuka Y, Nishikawa H, Okada T, Kanamaru H, Pak S, Shiba M, Suzuki H. Anti-vasospastic effects of epidermal growth factor receptor inhibitors after subarachnoid hemorrhage in mice. Mol Neurobiol. 2019;56:4730–40.

    Article  CAS  PubMed  Google Scholar 

  22. El-Karef A, Yoshida T, Gabazza EC, Nishioka T, Inada H, Sakakura T, Imanaka-Yoshida K. Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice. J Pathol. 2007;211:86–94.

    Article  CAS  PubMed  Google Scholar 

  23. Nakano F, Liu L, Kawakita F, Kanamaru H, Nakatsuka Y, Nishikawa H, Okada T, Shiba M, Suzuki H. Morphological characteristics of neuronal death after experimental subarachnoid hemorrhage in mice using double immunoenzymatic technique. J Histochem Cytochem. 2019;67:919–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Helbok R, Kofler M, Schiefecker AJ, Gaasch M, Rass V, Pfausler B, Beer R, Schmutzhard E. Clinical use of cerebral microdialysis in patients with aneurysmal subarachnoid hemorrhage-State of the art. Front Neurol. 2017;8:565. https://doi.org/10.3389/fneur.2017.00565.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Casillas-Espinosa PM, Ali I, O’Brien TJ. Neurodegenerative pathways as targets for acquired epilepsy therapy development. Epilepsia Open. 2020;5:138–54.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Isaac JT, Ashby MC, McBain CJ. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron. 2007;54:859–71.

    Article  CAS  PubMed  Google Scholar 

  27. Parfenova H, Fedinec A, Leffler CW. Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase. J Cereb Blood Flow Metab. 2003;23:190–7.

    Article  CAS  PubMed  Google Scholar 

  28. Casillas-Espinosa PM, Powell KL, O’Brien TJ. Regulators of synaptic transmission: roles in the pathogenesis and treatment of epilepsy. Epilepsia. 2012;53(Suppl 9):41–58.

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Luo C, Zhao M, Li Q, Hu R, Zhang JH, Liu Z, Feng H. Administration of a PTEN inhibitor BPV(pic) attenuates early brain injury via modulating AMPA receptor subunits after subarachnoid hemorrhage in rats. Neurosci Lett. 2015;588:131–6.

    Article  CAS  PubMed  Google Scholar 

  30. Turan N, Miller BA, Huie JR, Heider RA, Wang J, Wali B, Yousuf S, Ferguson AR, Sayeed I, Stein DG, Pradilla G. Effect of progesterone on cerebral vasospasm and neurobehavioral outcomes in a rodent model of subarachnoid hemorrhage. World Neurosurg. 2018;110:e150–9. https://doi.org/10.1016/j.wneu.2017.10.118.

    Article  PubMed  Google Scholar 

  31. Chen T, Zhu J, Wang YH. RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1-AMPAR pathway. FASEB J. 2020;34:15080–92.

    Article  CAS  PubMed  Google Scholar 

  32. Suzuki H, Ayer R, Sugawara T, Chen W, Sozen T, Hasegawa Y, Kanamaru K, Zhang JH. Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2010;38:612–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kondziella D, Friberg CK, Wellwood I, Reiffurth C, Fabricius M, Dreier JP. Continuous EEG monitoring in aneurysmal subarachnoid hemorrhage: a systematic review. Neurocrit Care. 2015;22:450–61.

    Article  CAS  PubMed  Google Scholar 

  34. Ferhat L, Chevassus-Au-Louis N, Khrestchatisky M, Ben-Ari Y, Represa A. Seizures induce tenascin-C mRNA expression in neurons. J Neurocytol. 1996;25:535–46.

    Article  CAS  PubMed  Google Scholar 

  35. Erdö F, Erdö SL. Bimoclomol protects against vascular consequences of experimental subarachnoid hemorrhage in rats. Brain Res Bull. 1998;45:163–6.

    Article  PubMed  Google Scholar 

  36. Colak A, Soy O, Karaoglan A, Akdemir O, Kokturk S, Sagmanligil A, Tasyurekli M. Effects of GYKI 52466 on early vasospasm in rats. Cent Eur Neurosurg. 2009;70:187–94.

    Article  CAS  PubMed  Google Scholar 

  37. Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl. 2013;197:19–24.

    Article  Google Scholar 

  38. Dohare P, Zia MT, Ahmed E, Ahmed A, Yadala V, Schober AL, Ortega JA, Kayton R, Ungvari Z, Mongin AA, Ballabh P. AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage. J Neurosci. 2016;36:3363–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004;61:657–68.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Chiduru Yamamoto-Nakamura (Department of Neurosurgery, Mie University Graduate School of Medicine) for her technical assistance.

Funding

This work was funded by JSPS KAKENHI Grant Number JP20K17963 to Dr. Kawakita and Taiju Life Social Welfare Foundation to Dr. Suzuki.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Fumihiro Kawakita, Hideki Kanamaru, Reona Asada & Hidenori Suzuki

  2. Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Kyoko Imanaka-Yoshida & Toshimichi Yoshida

Authors
  1. Fumihiro Kawakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideki Kanamaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reona Asada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyoko Imanaka-Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshimichi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hidenori Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Fumihiro Kawakita and Hidenori Suzuki contributed to the study conception and design. Fumihiro Kawakita, Hideki Kanamaru, Reona Asada, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, and Hidenori Suzuki performed material preparation, data collection, and analyses. Fumihiro Kawakita wrote the first draft of the manuscript. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Hidenori Suzuki.

Ethics declarations

Ethics Approval

All experiments of the present study were approved by the Animal Ethics Review Committee of Mie University.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 19924 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawakita, F., Kanamaru, H., Asada, R. et al. Inhibition of AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate) Receptor Reduces Acute Blood–Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice. Transl. Stroke Res. 13, 326–337 (2022). https://doi.org/10.1007/s12975-021-00934-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-021-00934-0

Keywords

Search

Navigation