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Apelin-13 attenuates early brain injury through inhibiting inflammation and apoptosis in rats after experimental subarachnoid hemorrhage

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Abstract

Background

Early brain injury (EBI) has been considered as the major contributor to the neurological dysfunction and poor clinical outcomes of subarachnoid hemorrhage (SAH). Studies showed that apelin-13 exhibits a neuroprotective effect in brain damage induced by cerebral ischemia. However, it remains unclear whether apelin-13 could exhibit the protective functions following SAH. The present study aimed to validate the neuroprotective role of apelin-13 in SAH, and further investigated the underlying mechanisms.

Methods and results

We constructed SAH rat model and we found that apelin-13 significantly alleviated neurological disorder and brain edema, improved memory deficits in SAH rats. Apelin-13 treatment decreased contents of TNF-α and IL-1β in cerebral spinal fluid of SAH rat by using ELISA. Apelin-13 treatment promoted the expression of APJ and Bcl-2, and decreased the level of active caspase-3 and Bax in the temporal cortex after SAH by using western blot. Also, apelin-13 attenuated the cortical cell death and neuronal degeneration as shown by TUNEL, FJB and Nissl staining. However, ML221, an inhibitor of APJ, significantly reversed all the above neuroprotective effects of apelin-13. Moreover, a neuron-microglia co-culture system, which mimic SAH in vitro, confirmed the protective effect of apelin-13 on neurons and the inhibitory effect on inflammation through apoptosis-related proteins.

Conclusions

These data demonstrated that apelin-13 exhibit a neuroprotective role after SAH through inhibition of apoptosis in an APJ dependent manner.

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Abbreviations

ANOVA:

Analysis of variance

APJ:

G protein-coupled receptor-apelin and angiotensin-1-like receptor

Bax:

Bcl-2 associated x protein

Bcl-2:

B-cell lymphoma 2

CSF:

Cerebral spinal fluid

DAPI:

4′,6-Diamidino-2-phenylindole

DMSO:

Dimethylsulfoxide

dUTP:

2′-Deoxyuridine 5′-Triphosphate

EBI:

Early brain injury

ER:

Endoplasmic reticulum

FJB:

Fluoro-Jade B

GLP-1R/PI3K/Akt:

Glucagon-like peptide-1/phosphatidylinositol 3-kinase/protein kinase B

IL-1β:

Interleukin-1β

PBS:

Phosphate buffer solution

ML221:

4-Oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate

MWM:

Morris water maze

Nrf2:

Nuclear factor erythroid 2-related factor-2

ROS:

Reactive oxide species

SAH:

Subarachnoid hemorrhage

SD:

Sprague–Dawley

TNF-α:

Tumor necrosis factor-α

WW/DW:

Wet weight/dry weight

Means ± SD:

Means ± standard deviation

IF:

Immunofluorescence

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

References

  1. Macdonald RL, Schweizer TA (2017) Spontaneous subarachnoid haemorrhage. Lancet 389:655–666. https://doi.org/10.1016/S0140-6736(16)30668-7

    Article  PubMed  Google Scholar 

  2. Balbi M, Vega MJ, Lourbopoulos A et al (2019) Long-term impairment of neurovascular coupling following experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. https://doi.org/10.1177/0271678X19863021

    Article  PubMed  PubMed Central  Google Scholar 

  3. Suzuki H (2019) Inflammation: a good research target to improve outcomes of poor-grade subarachnoid hemorrhage. Transl Stroke Res 10:597–600. https://doi.org/10.1007/s12975-019-00713-y

    Article  CAS  PubMed  Google Scholar 

  4. Mejdoubi M, Schertz M, Zanolla S et al (2018) Transoceanic management and treatment of aneurysmal subarachnoid hemorrhage: a 10-year experience. Stroke 49:127–132. https://doi.org/10.1161/STROKEAHA.117.017436

    Article  PubMed  Google Scholar 

  5. Xie YK, Zhou X, Yuan HT et al (2019) Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress. Neural Regen Res 14:1734–1742. https://doi.org/10.4103/1673-5374.257529

    Article  PubMed  PubMed Central  Google Scholar 

  6. Conzen C, Becker K, Albanna W et al (2019) The acute phase of experimental subarachnoid hemorrhage: intracranial pressure dynamics and their effect on cerebral blood flow and autoregulation. Transl Stroke Res 10:566–582. https://doi.org/10.1007/s12975-018-0674-3

    Article  CAS  PubMed  Google Scholar 

  7. Naraoka M, Fumoto T, Li Y et al (2019) The role of intracranial pressure and subarachnoid blood clots in early brain injury after experimental subarachnoid hemorrhage in rats. World Neurosurg 129:e63–e72. https://doi.org/10.1016/j.wneu.2019.05.009

    Article  PubMed  Google Scholar 

  8. Kleinz MJ, Davenport AP (2005) Emerging roles of apelin in biology and medicine. Pharmacol Ther 107:198–211. https://doi.org/10.1016/j.pharmthera.2005.04.001

    Article  CAS  PubMed  Google Scholar 

  9. Bao H, Yang X, Huang Y et al (2016) The neuroprotective effect of apelin-13 in a mouse model of intracerebral hemorrhage. Neurosci Lett 628:219–224. https://doi.org/10.1016/j.neulet.2016.06.046

    Article  CAS  PubMed  Google Scholar 

  10. Duan J, Cui J, Yang Z et al (2019) Neuroprotective effect of Apelin 13 on ischemic stroke by activating AMPK/GSK-3beta/Nrf2 signaling. J Neuroinflamm 16:24. https://doi.org/10.1186/s12974-019-1406-7

    Article  Google Scholar 

  11. Tian X, Sun L, Feng D et al (2017) HMGB1 promotes neurovascular remodeling via rage in the late phase of subarachnoid hemorrhage. Brain Res 1670:135–145. https://doi.org/10.1016/j.brainres.2017.06.001

    Article  CAS  PubMed  Google Scholar 

  12. Yang Y, Zhang X, Cui H et al (2014) Apelin-13 protects the brain against ischemia/reperfusion injury through activating PI3K/Akt and ERK1/2 signaling pathways. Neurosci Lett 568:44–49. https://doi.org/10.1016/j.neulet.2014.03.037

    Article  CAS  PubMed  Google Scholar 

  13. Xiong Q, He W, Wang H et al (2017) Effect of the spinal apelinAPJ system on the pathogenesis of chronic constriction injuryinduced neuropathic pain in rats. Mol Med Rep 16:1223–1231. https://doi.org/10.3892/mmr.2017.6734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang Z, Wu Y, Yuan S et al (2018) Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage. Brain Res 1701:112–125. https://doi.org/10.1016/j.brainres.2018.09.012

    Article  CAS  PubMed  Google Scholar 

  15. Li P, Li X, Deng P et al (2020) Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats. Aging 13:694–713. https://doi.org/10.18632/aging.202178

    Article  PubMed  PubMed Central  Google Scholar 

  16. Angelopoulou E, Paudel YN, Bougea A et al (2021) Impact of the apelin/APJ axis in the pathogenesis of Parkinson’s disease with therapeutic potential. J Neurosci Res. https://doi.org/10.1002/jnr.24895

    Article  PubMed  Google Scholar 

  17. O’Donnell LA, Agrawal A, Sabnekar P et al (2007) Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury. J Neurochem 102:1905–1917. https://doi.org/10.1111/j.1471-4159.2007.04645.x

    Article  CAS  PubMed  Google Scholar 

  18. Xu W, Gao L, Li T et al (2018) Apelin-13 alleviates early brain injury after subarachnoid hemorrhage via suppression of endoplasmic reticulum stress-mediated apoptosis and blood-brain barrier disruption: possible involvement of ATF6/CHOP pathway. Neuroscience 388:284–296. https://doi.org/10.1016/j.neuroscience.2018.07.023

    Article  CAS  PubMed  Google Scholar 

  19. Liu Y, Zhang T, Wang Y et al (2019) Apelin-13 attenuates early brain injury following subarachnoid hemorrhage via suppressing neuronal apoptosis through the GLP-1R/PI3K/Akt signaling. Biochem Biophys Res Commun 513:105–111. https://doi.org/10.1016/j.bbrc.2019.03.151

    Article  CAS  PubMed  Google Scholar 

  20. Xu W, Li T, Gao L et al (2019) Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats. J Neuroinflamm 16:247. https://doi.org/10.1186/s12974-019-1620-3

    Article  CAS  Google Scholar 

  21. Roche J, Rame C, Reverchon M et al (2017) Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. Reproduction 153:589–603. https://doi.org/10.1530/REP-16-0677

    Article  CAS  PubMed  Google Scholar 

  22. Datta A, Sarmah D, Mounica L et al (2020) Cell death pathways in ischemic stroke and targeted pharmacotherapy. Transl Stroke Res. https://doi.org/10.1007/s12975-020-00806-z

    Article  PubMed  Google Scholar 

  23. Aminyavari S, Zahmatkesh M, Farahmandfar M et al (2019) Protective role of Apelin-13 on amyloid beta25-35-induced memory deficit; involvement of autophagy and apoptosis process. Prog Neuropsychopharmacol Biol Psychiatry 89:322–334. https://doi.org/10.1016/j.pnpbp.2018.10.005

    Article  CAS  PubMed  Google Scholar 

  24. Zou Y, Wang B, Fu W et al (2016) Apelin-13 protects PC12 cells from corticosterone-induced apoptosis through PI3K and ERKs activation. Neurochem Res 41:1635–1644. https://doi.org/10.1007/s11064-016-1878-0

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Mr. Zhi Li for his linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81873741 & 82071297).

Author information

Author notes

  1. Xiaoyan Shen and Guiqiang Yuan have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, China

    Xiaoyan Shen, Guiqiang Yuan, Bing Li, Cheng Cao, Demao Cao, Jiang Wu, Xiang Li, Haiying Li, Haitao Shen, Zhong Wang & Gang Chen

  2. Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160, Pujian Road, Pudong District, Shanghai, 200127, China

    Xiaoyan Shen

  3. Department of Neurosurgery, Yancheng City No. 1 People’s Hospital, The Fourth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, China

    Bing Li

  4. Department of Neurocritical Intensive Care Unit, The Affiliated Jiangyin Hospital, School of Medicine, Southeast University, Jiangyin, Jiangsu Province, China

    Cheng Cao

  5. Department of Neurosurgery, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu Province, China

    Demao Cao

Authors
  1. Xiaoyan Shen
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Contributions

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: GC, ZW and HS. Acquisition of data: XS, and GY. Analysis and interpretation of data: BL, CC, DC, and JW. Drafting manuscript: XS, and GY. Administrative, technical, and material support: HL, and XL. Study supervision: GC, ZW and HS.

Corresponding authors

Correspondence to Haitao Shen or Zhong Wang.

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Conflict of interests

The authors declare that they have no conflict of interests.

Ethical approval

All animal experiments were approved by the Institutional Animal Care Committee of Soochow University and were performed in accordance with the guidelines of the National Institutes of Health.

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Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Supplementary file2 (DOCX 16 KB) Supplemental Table 1. Experimental mortality rate of rats.

11033_2021_7028_MOESM3_ESM.tif

Supplementary file3 (TIF 22704 KB) Supplemental Fig 1. The morphological changes observation of neuron and BV-2 cells in different groups.

11033_2021_7028_MOESM4_ESM.tif

Supplementary file4 (TIF 442 KB) Supplemental Fig 2. The viability of neuron and BV-2 cells in different groups was detected by MTT assay. *P < 0.05, **P < 0.01, ns P > 0.05.

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Shen, X., Yuan, G., Li, B. et al. Apelin-13 attenuates early brain injury through inhibiting inflammation and apoptosis in rats after experimental subarachnoid hemorrhage. Mol Biol Rep 49, 2107–2118 (2022). https://doi.org/10.1007/s11033-021-07028-y

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  • DOI: https://doi.org/10.1007/s11033-021-07028-y

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